1,2,3-Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia

ABSTRACT

The present invention relates to certain 1,2,3-trisubstituted aryl and heteroaryl derivatives of Formula (Ia) that are modulators of metabolism. 
     
       
         
         
             
             
         
       
     
     Accordingly, compounds of the present invention are useful in the prophylaxis or treatment of metabolic disorders and complications thereof, such as, diabetes and obesity.

FIELD OF THE INVENTION

The present invention relates to certain 1,2,3-trisubstituted aryl andheteroaryl derivatives that are modulators of glucose metabolism.Accordingly, compounds of the present invention are useful in theprophylaxis or treatment of metabolic disorders and complicationsthereof; such as, diabetes and obesity.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a serious disease afflicting over 100 millionpeople worldwide. In the United States, there are more than 12 milliondiabetics, with 600,000 new cases diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorderscharacterized by abnormal glucose homeostasis resulting in elevatedblood sugar. There are many types of diabetes, but the two most commonare Type I (also referred to as insulin-dependent diabetes mellitus orIDDM) and Type II (also referred to as non-insulin-dependent diabetesmellitus or NIDDM).

The etiology of the different types of diabetes is not the same;however, everyone with diabetes has two things in common: overproductionof glucose by the liver and little or no ability to move glucose out ofthe blood into the cells where it becomes the body's primary fuel.

People who do not have diabetes rely on insulin, a hormone made in thepancreas, to move glucose from the blood into the cells of the body.However, people who have diabetes either don't produce insulin or can'tefficiently use the insulin they produce; therefore, they can't moveglucose into their cells. Glucose accumulates in the blood creating acondition called hyperglycemia, and over time, can cause serious healthproblems.

Diabetes is a syndrome with interrelated metabolic, vascular, andneuropathic components. The metabolic syndrome, generally characterizedby hyperglycemia, comprises alterations in carbohydrate, fat and proteinmetabolism caused by absent or markedly reduced insulin secretion and/orineffective insulin action. The vascular syndrome consists ofabnormalities in the blood vessels leading to cardiovascular, retinaland renal complications. Abnormalities in the peripheral and autonomicnervous systems are also part of the diabetic syndrome.

People with IDDM, which accounts for about 5% to 10% of those who havediabetes, don't produce insulin and therefore must inject insulin tokeep their blood glucose levels normal. IDDM is characterized by low orundetectable levels of endogenous insulin production caused bydestruction of the insulin-producing β cells of the pancreas, thecharacteristic that most readily distinguishes IDDM from NIDDM. IDDM,once termed juvenile-onset diabetes, strikes young and older adultsalike.

Approximately 90 to 95% of people with diabetes have Type II (or NIDDM).NIDDM subjects produce insulin, but the cells in their bodies areinsulin resistant: the cells don't respond properly to the hormone, soglucose accumulates in their blood. NIDDM is characterized by a relativedisparity between endogenous insulin production and insulinrequirements, leading to elevated blood glucose levels. In contrast toIDDM, there is always some endogenous insulin production in NIDDM; manyNIDDM patients have normal or even elevated blood insulin levels, whileother NIDDM patients have inadequate insulin production (Rotwein, R. etal. N Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed with NIDDMare age 30 or older, and half of all new cases are age 55 and older.Compared with whites and Asians, NIDDM is more common among NativeAmericans, African-Americans, Latinos, and Hispanics. In addition, theonset can be insidious or even clinically inapparent, making diagnosisdifficult.

The primary pathogenic lesion on NIDDM has remained elusive. Many havesuggested that primary insulin resistance of the peripheral tissues isthe initial event. Genetic epidemiological studies have supported thisview. Similarly, insulin secretion abnormalities have been argued as theprimary defect in NIDDM. It is likely that both phenomena are importantcontributors to the disease process (Rimoin, D. L., et. al. Emery andRimoin's Principles and Practice of Medical Genetics 3^(rd) Ed.1:1401-1402 (1996)).

Many people with NIDDM have sedentery lifestyles and are obese; theyweigh approximately 20% more than the recommended weight for theirheight and build. Furthermore, obesity is characterized byhyperinsulinemia and insulin resistance, a feature shared with NIDDM,hypertension and atherosclerosis.

Obesity and diabetes are among the most common human health problems inindustrialized societies. In industrialized countries a third of thepopulation is at least 20% overweight. In the United States, thepercentage of obese people has increased from 25% at the end of the1970s, to 33% at the beginning the 1990s. Obesity is one of the mostimportant risk factors for NIDDM. Definitions of obesity differ, but ingeneral, a subject weighing at least 20% more than the recommendedweight for his/her height and build is considered obese. The risk ofdeveloping NIDDM is tripled in subjects 30% overweight, andthree-quarters with NIDDM are overweight.

Obesity, which is the result of an imbalance between caloric intake andenergy expenditure, is highly correlated with insulin resistance anddiabetes in experimental animals and human. However, the molecularmechanisms that are involved in obesity-diabetes syndromes are notclear. During early development of obesity, increase insulin secretionbalances insulin resistance and protects patients from hyperglycemia (LeStunff, et al. Diabetes 43, 696-702 (1989)). However, after severaldecades, β cell function deteriorates and non-insulin-dependent diabetesdevelops in about 20% of the obese population (Pederson, P. Diab. Metab.Rev. 5, 505-509 (1989)) and (Brancati, F. L., et al., Arch. Intern. Med.159, 957-963 (1999)). Given its high prevalence in modern societies,obesity has thus become the leading risk factor for NIDDM (Hill, J. O.,et al., Science 280, 1371-1374 (1998)). However, the factors whichpredispose a fraction of patients to alteration of insulin secretion inresponse to fat accumulation remain unknown.

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/m² (see TABLE below). There are problems with this definitionin that it does not take into account the proportion of body mass thatis muscle in relation to fat (adipose tissue). To account for this,obesity can also be defined on the basis of body fat content: greaterthan 25% and 30% in males and females, respectively.

CLASSIFICATION OF WEIGHT BY BODY MASS INDEX (BMI) BMI CLASSIFICATION<18.5 Underweight 18.5-24.9 Normal 25.0-29.9 Overweight 30.0-34.9Obesity (Class I) 35.0-39.9 Obesity (Class II) >40   Extreme Obesity(Class III)

As the BMI increases there is an increased risk of death from a varietyof causes that is independent of other risk factors. The most commondiseases with obesity are cardiovascular disease (particularlyhypertension), diabetes (obesity aggravates the development ofdiabetes), gall bladder disease (particularly cancer) and diseases ofreproduction. Research has shown that even a modest reduction in bodyweight can correspond to a significant reduction in the risk ofdeveloping coronary heart disease.

Compounds marketed as anti-obesity agents include Orlistat (XENICAL™)and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorptiondirectly and tends to produce a high incidence of unpleasant (thoughrelatively harmless) side-effects such as diarrhea. Sibutramine (a mixed5-HT/noradrenaline reuptake inhibitor) can increase blood pressure andheart rate in some patients. The serotonin releaser/reuptake inhibitorsfenfluramine (Pondimin™) and dexfenfluramine (Redux™) have been reportedto decrease food intake and body weight over a prolonged period (greaterthan 6 months). However, both products were withdrawn after reports ofpreliminary evidence of heart valve abnormalities associated with theiruse. Accordingly, there is a need for the development of a saferanti-obesity agent.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplication induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents by 35%. The incidence of coronary diseases is doubledin subjects less than 50 years of age who are 30% overweight. Thediabetes patient faces a 30% reduced lifespan. After age 45, people withdiabetes are about three times more likely than people without diabetesto have significant heart disease and up to five times more likely tohave a stroke. These findings emphasize the inter-relations betweenrisks factors for NIDDM and coronary heart disease and the potentialvalue of an integrated approach to the prevention of these conditionsbased on the prevention of these conditions based on the prevention ofobesity (Perry, I. J., et al., BMJ 310, 560-564 (1995)).

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous-system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

SUMMARY OF THE INVENTION

The present invention is drawn to compounds, which bind to and modulatethe activity of a GPCR referred to herein as RUP3, and uses thereof. Theterm RUP3, as used herein, includes the human sequences found inGeneBank accession number XM_(—)066873, naturally-occurring allelicvariants, mammalian orthologs, and recombinant mutants thereof. Apreferred human RUP3 for use in screening and testing of the compoundsof the invention is provided in the nucleotide sequence of Seq. ID.No:1and the corresponding amino acid sequence in Seq. ID.No:2.

One aspect of the present invention encompasses 1,2,3-trisubstitutedaryl and heteroaryl derivatives as shown in Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,

wherein:

-   -   A and B are independently C₁₋₅ alkylene optionally substituted        with 1 to 4 methyl groups;

D is O, S, S(O), S(O)₂, CR₂R₃ or N—R₂;

V is selected from the group consisting of C₁₋₃ alkylene, ethynylene andC₁₋₂ heteroalkylene wherein each are optionally substituted with 1 to 4substituents selected from the group consisting of C₁₋₃ alkyl, C₁₋₄alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen; or V is absent;W is NR₄, O, S, S(O) or S(O)₂; or W is absent;

X is N or CR₅;

Y is N or CR₆;

Z is selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino,C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₄₋₈diacylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl, heterocyclic,heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl, wherein C₁₋₈alkyl and C₁₋₅ acyl are each optionally substituted with 1, 2, 3 or 4groups selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy,C₁₋₄ alkoxy, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, formyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen,hydroxyl, hydroxylamino and nitro; or

Z is a group of Formula (A):

-   -   wherein:        R₇ is H, C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₈ is H, nitro or        nitrile;

Ar₁ is aryl or heteroaryl wherein each are optionally substituted withR₉-R₁₃; R₁ is selected from the group consisting of H, C₁₋₅ acyloxy,C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈dialkylamino, carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkylthio and hydroxyl;

R₂ is selected from the group consisting of H, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen,heteroaryl, hydroxyl and phenyl; and wherein C₁₋₈ alkyl, heteroaryl andphenyl are each optionally substituted with 1 to 5 substituents selectedfrom the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkylene, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro; or

R₂ is —Ar₂-Ar₃ wherein Ar₂ and Ar₃ are independently aryl or heteroaryleach optionally substituted with 1 to 5 substituents selected from thegroup consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or

R₂ is a group of Formula (B):

-   -   wherein:    -   R₁₄ is C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₁₅ is F, Cl, Br or        CN; or

R₂ is a group of Formula (C):

-   -   wherein:    -   G is C═O, CR₁₆R₁₇, O, S, S(O), S(O)₂; where R₁₆ and R₁₇ are        independently H or C₁₋₄ alkyl; and        Ar₄ is phenyl or heteroaryl optionally substituted with 1 to 5        substituents selected from the group consisting of C₁₋₅ acyl,        C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,        C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy,        carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆        dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆        dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkyl, C₁₋₄ haloalkylthio, halogen, heteroaryl, hydroxyl,        hydroxylamino and nitro;

R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy, halogen or hydroxyl;

R₄ is H or C₁₋₈ alkyl;

R₅ and R₆ are independently H, C₁₋₈ alkyl or halogen;

R₉ is selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy,C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, arylsulfonyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆ cycloalkyl, C₂₋₆ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, nitro, C₄₋₇oxo-cycloalkyl, phenoxy, phenyl, sulfonamide and sulfonic acid, andwherein C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfonamide,alkylsulfonyl, arylsulfonyl, heteroaryl, phenoxy and phenyl are eachoptionally substituted with 1 to 5 substituents selected independentlyfrom the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heteroaryl, heterocyclic,hydroxyl, nitro and phenyl; or

R₉ is a group of Formula (D):

-   -   wherein:    -   “p” and “r” are independently 0, 1, 2 or 3; and        -   R₁₈ is H, C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄            alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,            carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆            cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl or            phenyl, and wherein the heteroaryl and phenyl are each            optionally substituted with 1 to 5 substituents selected            independently from the group consisting of C₁₋₄ alkoxy,            amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino,            halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl; and            R₁₀-R₁₃ are independently selected form the group consisting            of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈            alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄            alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,            C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,            carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆            dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄            haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,            C₁₋₄ haloalkylthio, hydroxyl and nitro; or two adjacent            R₁₀-R₁₁ groups together with Ar₁ form a 5, 6 or 7 membered            cycloalkyl, cycloalkenyl or heterocyclic group wherein the            5, 6 or 7 membered group is optionally substituted with            halogen.

Some embodiments of the present invention include pharmaceuticalcompositions comprising at least one compound of the present inventionand a pharmaceutically acceptable carrier.

Some embodiments of the present invention include methods forprophylaxis or treatment of a metabolic disorder in an individualcomprising administering to the individual a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticalcomposition thereof.

Some embodiments of the present invention include methods of controllingor decreasing weight gain of an individual comprising administering tothe individual a therapeutically effective amount of a compound of thepresent invention or pharmaceutical composition thereof.

Some embodiments of the present invention include methods of modulatinga RUP3 receptor comprising contacting the receptor with a compound ofthe present invention.

Some embodiments of the present invention include methods of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention. In some embodiments, the compoundis an agonist. In some embodiments, the compound is an inverse agonist.

Some embodiments of the present invention include methods of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor is prophylaxis or treatment of a metabolic disorder.

Some embodiments of the present invention include methods of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor controls or reduces weight gain of the individual.

Some embodiments of the present invention include the use of compoundsof the present invention for production of a medicament for use inprophylaxis or treatment of a metabolic disorder.

Some embodiments of the present invention include the use of compoundsof the present invention for production of a medicament for use incontrolling or decreasing weight gain in an individual.

One aspect of the present invention pertains to compounds of the presentinvention, as described herein, for use in methods of treatment of thehuman or animal body by therapy.

One aspect of the present invention pertains to compounds of the presentinvention, as described herein, for use in methods of prophylaxis ortreatment of a metabolic disorder of the human or animal body bytherapy.

In some embodiments, the metabolic disorder is type I, type II diabetes,inadequate glucose tolerance, insulin resistance, hyperglycemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,dyslipidemia, syndrome X or metabolic syndrome.

One aspect of the present invention pertains to methods of producing apharmaceutical compositions comprising admixing at least one compound ofthe present invention and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows RT-PCR analysis of RUP3 expression in human tissues. Atotal of twenty-two (22) human tissues were analyzed.

FIG. 1B shows the cDNA Dot-Blot analysis of RUP 3 expression in humantissues.

FIG. 1C shows analysis of RUP3 by RT-PCR with isolated human pancreaticislets of Langerhans.

FIG. 1D shows analysis of RUP3 expression with cDNAs of rat origin byRT-PCR.

FIG. 2A shows a polyclonal anti-RUM antibody prepared in Rabbits.

FIG. 2B shows the expression of RUP3 in insulin-producing β cells ofpancreatic islets.

FIG. 3 shows functional activities of RUP3 In vitro.

FIG. 4A shows a RUP3 RNA blot.

FIG. 4B shows RUP3 agonist, Compound B84, stimulates cAMP production inHIT cells, at a level comparable to that seen with the adenyl cyclaseactivator forskolin.

FIG. 4C shows RUP3 agonist, Compound B84, stimulates insulin secretionin HIT cells exposed to 15 mM glucose, at a level comparable to thatseen with the adenylcyclase activator forskolin.

FIG. 4D shows two RUP3 compounds, Compounds A48 and A51 (at 10 μMconcentration), and the enhanced glucose-dependent insulin releasecompared to control.

FIG. 5A shows the In vivo effects of a RUP3 agonist (Compound B70) onglucose homeostasis in mice and specifically the effect by a RUP3agonist in a dose-dependent manner on the lowering of blood glucoseafter glucose challenge.

FIG. 5B shows the acute response of db mice to a RUP 3 agonist and Ex-4.FIG. 5B shows Compound B70 and Ex-4 significantly reduces glucose levelscompared to vehicle control.

FIG. 6 shows a representative scheme for the syntheses of compounds ofthe present invention.

DEFINITIONS

The scientific literature that has evolved around receptors has adopteda number of terms to refer to ligands having various effects onreceptors. For clarity and consistency, the following definitions willbe used throughout this patent document.

AGONISTS shall mean moieties that activate the intracellular responsewhen they bind to the receptor, or enhance GTP binding to membranes.

AMINO ACID ABBREVIATIONS used herein are set out in Table 1:

TABLE 1 ALANINE ALA A ARGININE ARG R ASPARAGINE ASN N ASPARTIC ACID ASPD CYSTEINE CYS C GLUTAMIC ACID GLU E GLUTAMINE GLN Q GLYCINE GLY GHISTIDINE HIS H ISOLEUCINE ILE I LEUCINE LEU L LYSINE LYS K METHIONINEMET M PHENYLALANINE PHE F PROLINE PRO P SERINE SER S THREONINE THR TTRYPTOPHAN TRP W TYROSINE TYR Y VALINE VAL V

Chemical Group, Moiety or Radical:

The term “C₁₋₅ acyl” denotes an alkyl radical attached to a carbonylwherein the definition of alkyl has the same definition as describedherein; some examples include formyl, acetyl, propionyl, butanoyl,iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, and the like.

The term “C₁₋₅ acyloxy” denotes an acyl radical attached to an oxygenatom wherein acyl has the same definition has described herein; someexamples include acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxyand the like.

The term “C₂₋₆ alkenyl” denotes a radical containing 2 to 6 carbonswherein at least one carbon-carbon double bond is present, someembodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, andsome embodiments have 2 carbons. Both E and Z isomers are embraced bythe term “alkenyl.” Furthermore, the term “alkenyl” includes di- andtri-alkenyls. Accordingly, if more than one double bond is present thenthe bonds may be all E or Z or a mixtures of E and Z. Examples of analkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl,2,4-hexadienyl and the like.

The term “C₁₋₄ alkoxy” as used herein denotes a radical alkyl, asdefined herein, attached directly to an oxygen atom. Example includemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxyand the like.

The term “C₁₋₈ alkyl” denotes a straight or branched carbon radicalcontaining 1 to 8 carbons, some embodiments are 1 to 6 carbons, someembodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons.Examples of an alkyl include methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, t-butyl, amyl, t-amyl, n-pentyl and the like.

The term “C₁₋₄ alkylcarboxamido” denotes a single alkyl group attachedto an amide, wherein alkyl has the same definition as found herein. TheC₁₋₅ alkylcarboxamido may be represented by the following:

Examples include N-methylcarboxamide, N-ethylcarboxamide,N-(iso-propyl)carboxamide and the like.

The term “C₁-C₃ alkylene” refers to a divalent straight carbon group,such as, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—.

The term “C₁₋₄ alkylsulfinyl” denotes an alkyl radical attached to asulfoxide radical of the formula: —S(O)— wherein the alkyl radical hasthe same definition as described herein. Examples includemethylsulfonyl, ethylsultinyl and the like.

The term “C₁₋₄ alkylsulfonamide” refers to the groups

The term “C₁₋₄ alkylsulfonyl” denotes an alkyl radical attached to asulfone radical of the formula: —S(O)₂— wherein the alkyl radical hasthe same definition as described herein. Examples includemethylsulfonyl, ethylsulfonyl and the like.

The term “C₁₋₄ alkylthio” denotes an alkyl radical attached to a sulfideof the formula: —S— wherein the alkyl radical has the same definition asdescribed herein. Examples include methylsulfanyl (i.e., CH₃S—),ethylsulfanyl, isopropylsulfanyl and the like.

The term “C₁₋₄ alkylthiocarboxamide” denotes a thioamide of thefollowing formulae:

The term “C₁₋₄ alkylthioureyl” denotes the group of the formula:

—NC(S)N— wherein one are both of the nitrogens are substituted with thesame or different alkyl group and alkyl has the same definition asdescribed herein. Examples of an alkylthioureyl include, CH₃NHC(O)NH—,NH₂C(O)NCH₃—, (CH₃)₂N(O)NH—, (CH₃)₂N(O)NH—, (C₁₋₁₃)₂N(O)NCH₃—,CH₃CH₂NHC(O)NH—, CH₃CH₂NHC(O)NCH₃—, and the like.

The term “C₁₋₄ alkylureyl” denotes the group of the formula: —NC(O)N—wherein one are both of the nitrogens are substituted with the same ordifferent alkyl group wherein alkyl has the same definition as describedherein. Examples of an alkylureyl include, CH₃NHC(O)NH—, NH₂C(O)NCH₃—,(CH₃)₂N(O)NH—, (C₁₋₁₃)₂N(O)NH—, (CH₃)₂N(O)NCH₃—, CH₃CH₂NHC(O)NH—,CH₃CH₂NHC(O)NCH₃—, and the like.

The term “C₂₋₆ alkynyl” denotes a radical containing 2 to 6 carbons andat least one carbon-carbon triple bond, some embodiments are 2 to 4carbons, some embodiments are 2 to 3 carbons, and some embodiments have2 carbons. Examples of an alkynyl include ethynyl, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl and the like. The term “alkynyl” includes di- and tri-ynes.

The term “amino” denotes the group —NH₂.

The term “C₁₋₄ alkylamino” denotes one alkyl radical attached to anamino radical wherein the alkyl radical has the same meaning asdescribed herein. Some examples include methylamino, ethylamino,propylamino and the like.

The term “aryl” denotes an aromatic ring radical containing 6 to 10 ringcarbons. Examples include phenyl and naphthyl.

The term “arylalkyl” defines a C₁-C₄ alkylene, such as —CH₂—, —CH₂CH₂—and the like, which is further substituted with an aryl group. Examplesof an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamido” denotes a single aryl group attached to theamine of an amide, wherein aryl has the same definition as found herein.The example is N-phenylcarboxamide.

The term “arylureyl” denotes the group —NC(O)N— where one of thenitrogens are substituted with an aryl.

The term “benzyl” denotes the group —CH₂C₆H₅.

The term “carbo-C₁₋₆-alkoxy” refers to an alkyl ester of a carboxylicacid, wherein the alkyl group is C₁₋₆. Examples include carbomethoxy,carboethoxy, carboisopropoxy and the like.

The term “carboxamide” refers to the group —CONH₂.

The term “carboxy” or “carboxyl” denotes the group —CO₂H; also referredto as a carboxylic acid.

The term “cyano” denotes the group —CN.

The term “C₃₋₇ cycloalkenyl” denotes a non-aromatic ring radicalcontaining 3 to 6 ring carbons and at least one double bond; someembodiments contain 3 to 5 carbons; some embodiments contain 3 to 4carbons. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclopentenyl, cyclohexenyl, and the like.

The term “C₃₋₇ cycloalkyl” denotes a saturated ring radical containing 3to 6 carbons; some embodiments contain 3 to 5 carbons; some embodimentscontain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

The term “C₃₋₆ cycloalkyl-C₁₋₃-alkylene” denotes a saturated ringradical containing 3 to 6 carbons bonded to a C₁₋₃-alkylene as describedherein; some embodiments contain 3 to 5 carbons; some embodimentscontain 3 to 4 carbons. Examples include cyclopropyl-CH₂—,cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—, cyclohexyl-CH₂—,and the like.

The term “C₄₋₈ diacylamino” denotes an amino group bonded with two acylgroups defined herein wherein the acyl groups may be the same ordifferent, such as:

Represented dialkylamino groups include diacetylamino, dipropionylamino,acetylpropionylamino and the like.

The term “C₂₋₆ dialkylamino” denotes an amino substituted with two ofthe same or different alkyl radicals wherein alkyl radical has the samedefinition as described herein. Some embodiments are C₂₋₄ dialkylaminogroups. Some examples include dimethylamino, methylethylamino,diethylamino and the like.

The term “C₁₋₄ dialkylcarboxamido” or “C₁₋₄ dialkylcarboxamide” denotestwo alkyl radicals, that are the same or different, attached to an amidegroup, wherein alkyl has the same definition as described herein. A C₁₋₄dialkylcarboxamido may be represented by the following groups:

Examples of a dialkylcarboxamide include N,N-dimethylcarboxamide,N-methyl-N-ethylcarboxamide and the like.

The term “C₂₋₆ dialkylsulfonamide” refers to one of the following groupsshown below:

The term “C₁₋₄ dialkylthiocarboxamido” or “C₁₋₄ dialkylthiocarboxamide”denotes two alkyl radicals, that are the same or different, attached toa thioamide group, wherein alkyl has the same definition as describedherein. A C₁₋₄ dialkylthiocarboxamido may be represented by thefollowing groups:

Examples of a dialkylthiocarboxamide includeN,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and thelike.

The term “C₁₋₄ dialkylsulfonylamino” refers to an amino group bondedwith two C₁₋₄ alkylsulfonyl groups as defined herein.

The term “ethynylene” refers to the carbon-carbon triple bond group asrepresented below:

The term “formyl” refers to the group —CHO.

The term “C₁₋₄ haloalkoxy” denotes a haloalkyl, as defined herein, thatis directly attached to an oxygen to form a difluoromethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.

The term “C₁₋₄ haloalkyl” denotes an alkyl group, defined herein,wherein the alkyl is substituted with one halogen up to fullysubstituted represented by the formula C_(n)F_(2n+1); when more than onehalogen is present they may be the same or different and selected fromF, Cl, Br or I. Some embodiments are 1 to 3 carbons. Examples includefluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like.

The term “C₁₋₄ haloalkylcarboxamide” denotes an alkylcarboxamide group,defined herein, wherein the alkyl is substituted with one halogen up tofully substituted represented by the formula C_(n)F_(2n+1) and “n” is 1,2, 3 or 4. When more than one halogen is present they may be the same ordifferent and selected from F, Cl, Br or I. Examples include2-fluoroacetyl, 2,2-difluoroacetyl, 2,2,2-trifluoroacetyl,2-chloro-2,2-difluoroacetyl, 3,3,3-trifluoropropionyl,2,2,3,3,3-pentafluoropropionyl and the like.

The term “C₁₋₄ haloalkylsulfinyl” denotes a haloalkyl radical attachedto a sulfoxide of the formula: —S(O)— wherein the alkyl radical has thesame definition as described herein. Examples includetrifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl,2,2-difluoroethylsulfinyl and the like.

The term “C₁₋₄ haloalkylsulfonyl” denotes a haloalkyl attached to asulfone of the formula: —S(O)₂— wherein haloalkyl has the samedefinition as described herein. Examples includetrifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,2,2-difluoroethylsulfonyl and the like.

The term “C₁₋₄ haloalkylthio” denotes an alkylthio radical substitutedwith one or more halogens. Examples include trifluoromethylthio,1,1-difluoroethylthio, 2,2,2-trifluoroethylthio and the like.

The term “halogen” or “halo” denotes to a fluoro, chloro, bromo or iodogroup.

The term “C₁₋₂ heteroalkylene” refers to a C₁₋₂ alkylene bonded to aheteroatom selected from O, S, S(O), S(O)₂ and NH. Some representedexamples include the groups of the following formulae:

and the like

The term “heteroaryl” denotes an aromatic ring system that may be asingle ring, two fused rings or three fused rings containing carbons andat least one ring heteroatom selected from O, S and N. Examples ofheteroaryl groups include, but not limited to, pyridyl, benzofuranyl,pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole,benzothiazole, 1H-benzimidazole, isoquinoline, quinazoline, quinoxaline,1H-imidazolyl, [1,2,4]triazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,pyrrolyl, pyrazolyl, 1H-pyrazolyl, imidazolyl, oxazolyl, oxazolyl,[1,3,4]oxadiazolyl, [1,3,4]thiadiazolyl, [1,2,4]oxadiazolyl,[1,2,4]thiadiazolyl, tetrazolyl, 1,3-dioxo-1,3-dihydro-isoindolyl,[1,2,3]thiadiazol-4-yl and the like.

The term “heterocyclic” denotes a non-aromatic carbon ring (i.e.,cycloalkyl or cycloalkenyl as defined herein) wherein one, two or threering carbons are replaced a heteroatom, such as, O, S, N, wherein the Ncan be optionally substituted with H, C₁₋₄ acyl or C₁₋₄ alkyl, and ringcarbon atoms optionally substituted with oxo or a thiooxo thus forming acarbonyl or thiocarbonyl group. The heterocyclic group is a 3-, 4-, 5-,6- or 7-membered containing ring. Examples of a heterocyclic groupinclude but not limited to aziridin-1-yl, aziridin-2-yl, azetidin-1-yl,azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-4-yl,morpholin-4-yl, piperzin-1-yl, piperzin-4-yl, pyrrolidin-1-yl,pyrrolidin-3-yl, [1,3]-dioxolan-2-yl and the like. Additional examplesof heterocyclic groups are shown in Tables 2B, 2C, 2D, 2E, 2F and 2G,infra.

The term “heterocycliccarboxamido” denotes a heterocyclic group with aring nitrogen where the ring nitrogen is bonded directly to the carbonylforming an amide. Examples include:

and the like.

The term “heterocyclicsulfonyl” denotes a heterocyclic group with a ringnitrogen where the ring nitrogen is bonded directly to an SO₂ groupforming an sulfonamide. Examples include:

and the like.

The term “hydroxyl” refers to the group —OH.

The term “hydroxylamino” refers to the group —NHOH.

The term “nitro” refers to the group —NO₂.

The term “C₄₋₇ oxo-cycloalkyl” refers to a C₄₋₇ cycloalkyl, as definedherein, wherein one of the ring carbons is replaced with a carbonyl.Examples of C₄₋₇ oxo-cycloalkyl include but are not limited to:2-oxo-cyclobutyl, 3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl,and the like and represented the following structures respectively:

The term “perfluoroalkyl” denotes the group of the formula—C_(n)F_(2n+1); stated differently, a perfluoroalkyl is an alkyl asdefined herein wherein the alkyl is fully substituted with fluorineatoms and is therefore considered a subset of haloalkyl. Examples ofperfluoroalkyls include CF₃, CF₂CF₃, CF₂CF₂CF₃, CF(CF₃)₂, CF₂CF₂CF₂CF₃,CF₂CF(CF₃)₂, CF(CF₃)CF₂CF₃ and the like.

The term “phenoxy” refers to the group C₆H₅O—.

The term “phenyl” refers to the group C₆H₅—.

The term“sulfonic acid” refers to the group —SO₃H.

The term “tetrazolyl” refers to the five membered heteroaryl of thefollowing formulae:

-   -   In some embodiments, the tetrazolyl group is further substituted        at either the 1 or 5 position respectively.        -   The term “thiol” denotes the group —SH.

CODON shall mean a grouping of three nucleotides (or equivalents tonucleotides) which generally comprise a nucleoside (adenosine (A),guanosine (G), cytidine (C), uridine (U) and thymidine (T)) coupled to aphosphate group and which, when translated, encodes an amino acid.

COMPOSITION shall mean a material comprising at least two compounds ortwo components; for example, and not limitation, a PharmaceuticalComposition is a Composition.

COMPOUND EFFICACY shall mean a measurement of the ability of a compoundto inhibit or stimulate receptor functionality, as opposed to receptorbinding affinity.

CONSTITUTIVELY ACTIVATED RECEPTOR shall mean a receptor subject toconstitutive receptor activation.

CONSTITUTIVE RECEPTOR ACTIVATION shall mean stabilization of a receptorin the active state by means other than binding of the receptor with itsendogenous ligand or a chemical equivalent thereof.

CONTACT or CONTACTING shall mean bringing at least two moietiestogether, whether in an in vitro system or an in vivo system.

ENDOGENOUS shall mean a material that a mammal naturally produces.ENDOGENOUS in reference to, for example and not limitation, the term“receptor” shall mean that which is naturally produced by a mammal (forexample, and not limitation, a human) or a virus.

In contrast, the term NON-ENDOGENOUS in this context shall mean thatwhich is not naturally produced by a mammal (for example, and notlimitation, a human) or a virus. For example, and not limitation, areceptor which is not constitutively active in its endogenous form, butwhen manipulated becomes constitutively active, is most preferablyreferred to herein as a “non-endogenous, constitutively activatedreceptor.” Both terms can be utilized to describe both “in vivo” and “invitro” systems. For example, and not a limitation, in a screeningapproach, the endogenous or non-endogenous receptor may be in referenceto an in vitro screening system. As a further example and notlimitation, where the genome of a mammal has been manipulated to includea non-endogenous constitutively activated receptor, screening of acandidate compound by means of an in vivo system is viable.

INDIVIDUAL as used herein refers to any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

INHIBIT or INHIBITING, in relationship to the term “response” shall meanthat a response is decreased or prevented in the presence of a compoundas opposed to in the absence of the compound.

INVERSE AGONISTS shall mean moieties that bind the endogenous form ofthe receptor or to the constitutively activated form of the receptor,and which inhibit the baseline intracellular response initiated by theactive form of the receptor below the normal base level of activitywhich is observed in the absence of agonists or partial agonists, ordecrease GTP binding to membranes. Preferably, the baselineintracellular response is inhibited in the presence of the inverseagonist by at least 30%, more preferably by at least 50%, and mostpreferably by at least 75%, as compared with the baseline response inthe absence of the inverse agonist.

LIGAND shall mean an endogenous, naturally occurring molecule specificfor an endogenous, naturally occurring receptor.

As used herein, the terms MODULATE or MODULATING shall mean to refer toan increase or decrease in the amount, quality, response or effect of aparticular activity, function or molecule.

PHARMACEUTICAL COMPOSITION shall mean a composition comprising at leastone active ingredient, whereby the composition is amenable toinvestigation for a specified, efficacious outcome in a mammal (forexample, and not limitation, a human). Those of ordinary skill in theart will understand and appreciate the techniques appropriate fordetermining whether an active ingredient has a desired efficaciousoutcome based upon the needs of the artisan.

DETAILED DESCRIPTION Compound of the Present Invention

One aspect of the present invention pertains to certain1,2,3-trisubstituted aryl and heteroaryl derivatives as shown in Formula(Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein A, B, D, V, W, X, Y, Z Ar₁, and R₁ are as described herein,supra and infra.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

One aspect of the present invention encompasses N-oxides of1,2,3-trisubstituted aryl and heteroaryl derivatives of Formula (Ia).

One aspect of the present invention encompasses 1,2,3-trisubstitutedaryl and heteroaryl derivatives as shown in Formula (Ia) wherein W isNR₄ and compounds may be represented by Formula (Ib) as shown below:

wherein each variable in Formula (Ib) has the same meaning as describedherein. In some embodiments, R₄ is H. In some embodiments, R₄ is CH₃ orCH₂CH₃.

One aspect of the present invention encompasses 1,2,3-trisubstitutedaryl and heteroaryl derivatives as shown in Formula (Ia) wherein W is O,(i.e., an oxygen atom) and compounds may be represented by Formula (Ic)as shown below:

wherein each variable in Formula (Ic) has the same meaning as describedherein.

One aspect of the present invention encompasses 1,2,3-trisubstitutedaryl and heteroaryl derivatives as shown in Formula (Ia) wherein W is S,S(O) or S(O)₂ and compounds may be represented by Formulae (Id), (Ie)and (If) respectively as shown below:

wherein each variable in Formulae (Id), (Ie) and (If) has the samemeaning as described herein.

One aspect of the present invention encompasses 1,2,3-trisubstitutedaryl and heteroaryl derivatives as shown in Formula (Ia) wherein W isabsent and compounds may be represented by Formula (Ig) as shown below:

wherein each variable in Formula (Ig) has the same meaning as describedherein. In some embodiments, compounds of the present invention are ofFormula (Ig) wherein V is absent and accordingly these compounds may berepresented by Formula (Ih) as shown below:

wherein each variable in Formula (Ih) has the same meaning as describedherein.

One aspect of the present invention encompasses 1,2,3-trisubstitutedaryl and heteroaryl derivatives as shown in Formula (Ia) wherein W isabsent and V is ethynylene. Compounds may be represented by Formula (Ii)as shown below:

wherein each variable in Formula (Ii) has the same meaning as describedherein.

In some embodiments, V is C₁₋₃ alkylene optionally substituted with 1 to4 substituents selected from the group consisting of C₁₋₃ alkyl, C₁₋₄alkoxy and halogen. In some embodiments, V is a methylene group (i.e.,—CH₂—). In some embodiments, V is an ethylene group (i.e., —CH₂CH₂—). Insome embodiments, V is a methylene and W is an oxygen atom. In someembodiments, V is methylene and W is a NR₄ group. In some embodiments, Vis methylene and W is a NH group. In some embodiments, V is ethylene andW is an oxygen atom. In some embodiments, V is ethylene and W is a NR₄group. In some embodiments, V is ethylene and W is a NH group.

In some embodiments, V is C₁₋₂ heteroalkylene optionally substitutedwith 1 to 4 substituents selected from the group consisting of C₁₋₃alkyl, C₁₋₄ alkoxy and halogen. In some embodiments, V is —OCH₂CH₂—. Insome embodiments, V is —OCH₂CH₂— and W is an oxygen atom and may berepresented by the formula: —OCH₂CH₂O—. In some embodiments, V is—OCH₂CH₂— and W is a NH group and may be represented by the formula:—OCH₂CH₂NH—.

In some embodiments, V is absent and may be represented by Formula (Ij)as shown below:

wherein each variable in Formula (Ij) has the same meaning as describedherein.

In some embodiments, A and B are both methylene wherein A and B areoptionally substituted with 1 to 2 methyl groups and therefore form afour-membered nitrogen containing ring. In some embodiments, compoundsof the invention may be represented by Formula (Ik) as shown below:

wherein each variable in Formula (Ik) has the same meaning as describedherein. In some embodiments, D is —CHR₂—.

In some embodiments, A is ethylene and B is methylene wherein A isoptionally substituted with 1 to 4 methyl groups and B is optionallysubstituted with 1 to 2 methyl groups. In some embodiments, compounds ofthe invention may be represented by Formula (Im) as shown below:

wherein each variable in Formula (Im) has the same meaning as describedherein. In some embodiments, D is —CHR₂—. In some embodiments, R₂ isC₁₋₄ alkylsulfonyl.

In some embodiments, A is propylene and B is methylene wherein A isoptionally substituted with 1 to 4 methyl groups and B is optionallysubstituted with Ito 2 methyl groups. In some embodiments, compounds ofthe invention may be represented by Formula (In) as shown below:

wherein each variable in Formula (In) has the same meaning as describedherein. In some embodiments, D is —CHR₂—.

In some embodiments, A and B are both ethylene wherein A and B areoptionally substituted with 1 to 4 methyl groups. In some embodiments,compounds of the invention may be represented by Formula (Io) as shownbelow:

wherein each variable in Formula (Io) has the same meaning as describedherein. In some embodiments, D is —CHR₂—.

In some embodiments, A is propylene and B is ethylene wherein A and Bare optionally substituted with 1 to 4 methyl groups. In someembodiments, compounds of the invention may be represented by Formula(Ip) as shown below:

wherein each variable in Formula (Ip) has the same meaning as describedherein. In some embodiments, D is —CHR₂—.

In some embodiments, A and B are both propylene wherein A and B areoptionally substituted with 1 to 4 methyl groups. In some embodiments,compounds of the invention may be represented by Formula (Iq) as shownbelow:

wherein each variable in Formula (Iq) has the same meaning as describedherein. In some embodiments, D is —CHR₂—.

In some embodiments, D is O, S, S(O) or S(O)₂. In some embodiments, D isS, S(O) or S(O)₂; and A and B are independently optionally substitutedwith 1 or 2 methyl groups. In some embodiments, A and B are ethylenegroups. In some embodiments, A and B are ethylene groups substitutedwith 2 methyl groups and D is an oxygen atom (i.e., forming a2,6-dimethyl-morpholin-4-yl group).

In some embodiments, D is CR₂R₃.

In some embodiments, R₂ is selected from the group consisting of H, C₁₋₅acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkoxy, haloalkyl, halogen and hydroxyl.

In some embodiments, R₂ is selected from the group consisting ofC(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂CH₂CH₂CH₃,OC(O)CH₃, OC(O)CH₂CH₃, OC(O)CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃,OCH(CH₃)₂, OCH₂(CH₂)₂CH₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, CH₂(CH₂)₃CH₃, C(O)NHCH₃, C(O)NHCH₂CH₃,C(O)NHCH₂CH₂CH₃, C(O)NHCH(CH₃)₂, C(O)NHCH₂(CH₂)₂CH₃, CO₂CH₃, CO₂CH₂CH₃,CO₂CH₂CH₂CH₃, CO₂CH(CH₃)₂ and CO₂CH₂(CH₂)₂CH₃.

In some embodiments, R₂ is selected from the group consisting ofC(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂CH₂CH₂CH₃,OC(O)CH₃, OC(O)CH₂CH₃, OC(O)CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃,OCH(CH₃)₂, OCH₂(CH₂)₂CH₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, CH₂(CH₂)₃CH₃, C(O)NH₂, CO₂CH₃, CO₂CH₂CH₃,CO₂CH₂CH₂CH₃, CO₂CH(CH₃)₂, CO₂CH₂(CH₂)₂CH₃, and CO₂H.

In some embodiments, R₂ is selected from the group consisting of SCH₃,SCH₂CH₃, SCH₂CH₂CH₃, SCH(CH₃)₂, SCH₂(CH₂)₂CH₃, S(O)CH₃, S(O)CH₂CH₃,S(O)CH₂CH₂CH₃, S(O)CH(CH₃)₂, S(O)CH₂(CH₂)₂CH₃, S(O)₂CH₃, S(O)₂CH₂CH₃,S(O)₂CH₂CH₂CH₃, S(O)₂CH(CH₃)₂, S(O)₂CH₂(CH₂)₂CH₃, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, OCF₃, OCHF₂, CF₃, CHF₂ and F.

In some embodiments, R₂ is selected from the group consisting ofS(O)₂CH₃, S(O)₂CH₂CH₃, S(O)₂CH₂CH₂CH₃, S(O)₂CH(CH₃)₂, S(O)₂CH₂(CH₂)₂CH₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, and F.

In some embodiments, R₂ is C₁₋₈ alkyl, or heteroaryl each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfonyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkylene, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, andhydroxyl.

In some embodiments, R₂ is selected from the group consisting ofCH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃, CH₂CH₂OCH₂CH₃,CH₂CH₂OCH₂CH₂C₁₋₁₃, CH₂OCH(CH₃)₂, CH₂OCH₂CH(CH₃)₂, CH₂CO₂H, CH₂CH₂CO₂H,CH₂OH, CH₂CH₂OH and CH₂CH₂CH₂OH.

In some embodiments, R₂ is C₁₋₃ alkyl, heteroaryl or phenyl eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁, haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro.

In some embodiments, R₂ is selected from the group consisting ofCH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃, CH₂CH₂OCH₂CH₃,CH₂CH₂OCH₂CH₂CH₃, CH₂OCH(CH₃)₂, CH₂OCH₂CH(CH₃)₂, CH₂CO₂H, CH₂CH₂CO₂H,CH₂OH, CH₂CH₂OH and CH₂CH₂CH₂OH.

In some embodiments, R₂ is selected from the group consisting ofCH₂SCH₃, CH₂SCH₂CH₃, CH₂SCH₂CH₂CH₃, CH₂SCH(CH₃)₂, CH₂SCH₂(CH₂)₂CH₃,CH₂CH₂SCH₃, CH₂CH₂SCH₂CH₃, CH₂CH₂SCH₂CH₂CH₃, CH₂CH₂SCH(CH₃)₂,CH₂CH₂SCH₂(CH₂)₂CH₃, CH₂S(O)CH₃, CH₂S(O)CH₂CH₃, CH₂S(O)CH₂CH₂CH₃,CH₂S(O)CH(CH₃)₂, CH₂S(O)CH₂(CH₂)₂CH₃, CH₂CH₂S(O)CH₃, CH₂CH₂S(O)CH₂CH₃,CH₂CH₂S(O)CH₂CH₂CH₃, CH₂CH₂S(O)CH(CH₃)₂, CH₂CH₂S(O)CH₂(CH₂)₂CH₃,CH₂S(O)₂CH₃, CH₂S(O)₂CH₂CH₃, CH₂S(O)₂CH₂CH₂CH₃, CH₂S(O)₂CH(CH₃)₂,CH₂S(O)₂CH₂(CH₂)₂CH₃, CH₂CH₂S(O)₂CH₃, CH₂CH₂S(O)₂CH₂CH₃,CH₂CH₂S(O)₂CH₂CH₂CH₃, CH₂CH₂S(O)₂CH(CH₃)₂ and CH₂CH₂S(O)₂CH₂(CH₂)₂CH₃.

In some embodiments, R₂ is selected from the group consisting ofCH₂OCH₂-cyclopropyl, CH₂OCH₂-cyclobutyl, CH₂OCH₂-cyclopentyl,CH₂OCH₂-cyclohexyl, CH₂OCH₂CH₂-cyclopropyl, CH₂OCH₂CH₂-cyclobutyl,CH₂OCH₂CH₂-cyclopentyl, CH₂OCH₂CH₂-cyclohexyl, CH₂CH₂OCH₂-cyclopropyl,CH₂CH₂OCH₂-cyclobutyl, CH₂CH₂OCH₂-cyclopentyl, CH₂CH₂OCH₂-cyclohexyl,CH₂CH₂OCH₂CH₂-cyclopropyl, CH₂CH₂OCH₂CH₂-cyclobutyl,CH₂CH₂OCH₂CH₂-cyclopentyl and CH₂CH₂OCH₂CH₂-cyclohexyl.

In some embodiments, R₂ is selected from the group consisting of1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,4-triazol-5-yl and 1,2,4-triazol-1-yl,3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,3-ethyl-1,2,4-oxadiazol-5-yl, 5-ethyl-1,2,4-oxadiazol-3-yl,5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl,3-methyl-1,2,4-triazol-5-yl, 3-ethyl-1,2,4-triazol-5-yl,3-methyl-1,2,4-triazol-1-yl, 3-ethyl-1,2,4-triazol-1-yl,5-methyl-1,2,4-triazol-1-yl and 5-ethyl-1,2,4-triazol-1-yl.

In some embodiments, R₂ is selected from the group consisting of1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl,3-isopropyl-1,2,4-oxadiazol-5-yl, 3-propyl-1,2,4-oxadiazol-5-yl,3-t-butyl-1,2,4-oxadiazol-5-yl, and 3-cyclopropyl-1,2,4-oxadiazol-5-yl.

In some embodiments, R₂ is selected from the group consisting of3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl,3-propyl-1,2,4-oxadiazol-5-yl, 3-isopropyl-1,2,4-oxadiazol-5-yl,3-butyl-1,2,4-oxadiazol-5-yl, and 3-(t-butyl)-1,2,4-oxadiazol-5-yl.

In some embodiments, R₂ is a heteroaryl comprising 5-atoms in thearomatic ring and are represented by the following formulae:

TABLE 2A

wherein the 5-membered heteroaryl is bonded at any available position ofthe ring, for example, a imidazolyl ring can be bonded at one of thering nitrogens (i.e., imidazol-1-yl group) or at one of the ring carbons(i.e., imidazol-2-yl, imidazol-4-yl or imidazol-5-yl group).

In some embodiments, R₂ is a 5-membered heteroaryl optionallysubstituted with 1 to 4 substituents selected from the group consistingof C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino,C₂₋₆ dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro.

In some embodiments, compounds of the present invention are of thefollowing formula:

wherein R₂ is a 5-membered heteroaryl optionally substituted with 1 to 4substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro; and R₃ is hydrogen or C₁₋₄ alkyl.

In some embodiments, R₂ is a 5-membered heteroaryl optionallysubstituted with 1 or 2 substituents selected from the group consistingof C₁₋₈ alkyl, C₁₋₄ haloalkyl and halogen; and R₃ is hydrogen.

In some embodiments, R₂ is a 5-membered heteroaryl optionallysubstituted with for 2 C₁₋₈ alkyl substituents; and R₃ is hydrogen.

In some embodiments, R₂ is a 5-membered heteroaryl optionallysubstituted with CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, C(CH₃)₃; and R₃ ishydrogen.

In some embodiments, R₂ is a fused heteroaryl group containing toaromatic rings wherein at least one is a heteroaryl ring, such as,benzofuranyl, benzimidazole, benzoxazole, benzothiazole, indole,benzothiophenyl. In some embodiments, R₂ is a benzofuran-2-yl group.

In some embodiments, R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2B.

TABLE 2B

It is understood that any one of the heterocyclic groups shown in TABLES2B to 2E may be bonded at any available ring carbon or ring nitrogen asallowed by the respective formula. For example, a2,5-dioxo-imidazolidinyl group may be bonded at the ring carbon or ateither of the two ring nitrogens to give the following formulaerespectively:

In some embodiments, R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2C.

TABLE 2C

In some embodiments, R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2D.

TABLE 2D

In some embodiments, R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2E.

TABLE 2E

In some embodiments, R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2F wherein the C₁₋₆ alkyl group on the respectivering nitrogen atoms may be the same or different.

TABLE 2F

In some embodiments, R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2G wherein the C₁₋₆ alkyl group on the respectivering nitrogen atoms may be the same or different.

TABLE 2G

In some embodiments, D is CR₂R₃ and R₂ is —Ar₂-Ar₃ wherein Ar₂ and Ar₃are independently aryl or heteroaryl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, halogen, hydroxyl and nitro. In some embodiments, Ar₂ is aheteroaryl and Ar₃ is phenyl. In some embodiments, compounds of thepresent invention are represented by Formula (Ir) as shown below:

wherein each variable in Formula (Ir) has the same meaning as describedherein. In some embodiments, compounds of the present invention are ofFormula (Ir) wherein R₃ is H.

In some embodiments, Ar₂ is a heteroaryl comprising 5-atoms in thearomatic ring and are represented by the following formulae:

TABLE 3

wherein the 5-membered heteroaryl is bonded at any available position ofthe ring, for example, a imidazolyl ring can be bonded at one of thering nitrogens (i.e., imidazol-1-yl group) or at one of the ring carbons(i.e., imidazol-2-yl, imidazol-4-yl or imidazol-5-yl group) and Ar₃ isbonded to any remaining available ring atom.

In some embodiments, Ar₂ is a heteroaryl and Ar₃ is phenyl. In someembodiments, the heteroaryl and phenyl are optionally substituted with 1to 5 substituents selected from the group consisting of H, C₁₋₄ alkoxy,C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen,hydroxyl and nitro.

In some embodiments, D is CR₂R₃ and R₂ is Formula (B):

wherein:

R₁₄ is C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₁₅ is F, Cl, Br or CN. Insome embodiments, R₁₄ is C₁₋₈ alkyl and R₁₅ is F, Cl or CN.

In some embodiments, D is CR₂R₃ and R₂ is Formula (C):

wherein:

G is C═O, CR₁₆R₁₇, O, S, S(O), S(O)₂; where R₁₆ and R₁₇ areindependently H or C₁₋₈ alkyl; and Ar₄ is phenyl or heteroaryloptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro.

In some embodiments, R₂ is Formula (C) wherein G is C═O, CR₁₆R₁₇, O, S,S(O), S(O)₂; wherein R₁₅ and R₁₇ are independently H or C₁₋₂ alkyl; andAr₄ is phenyl or heteroaryl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, and halogen.

In some embodiments, G is C═O, CH₂ or O. In some embodiments, G is S,S(O) or S(O)₂.

In some embodiments, Ar₄ is selected from the group consisting ofpyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments,Ar₄ is 2-pyridyl.

In some embodiments, compounds of the present invention are representedby Formula (Is) as shown below:

wherein each variable in Formula (Is) has the same meaning as describedherein.

In some embodiments, D is CR₂R₃, R₂ is Formula (C) and G is C═O, CR₁₆R₁₇or O. In some embodiments, Ar₄ is phenyl optionally substituted with 1to 5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro.

In some embodiments, Ar₄ is phenyl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, halogen and hydroxyl.

In some embodiments, Ar₄ is phenyl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl, halogen andhydroxyl.

In some embodiments, Ar₄ is heteroaryl optionally substituted with 1 to5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro.

In some embodiments, Ar₄ is heteroaryl optionally substituted with 1 to5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, halogen and hydroxyl.

In some embodiments, Ar₄ is heteroaryl optionally substituted with 1 to5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl, halogen andhydroxyl.

In some embodiments, Ar₄ is a 5-membered heteroaryl, for example, asshown in TABLE 2A supra. In some embodiments, Ar₄ is a 6-memberedheteroaryl, for example, the 6-membered heteroaryls as shown in TABLE 4:

TABLE 4

wherein the heteroaryl group is bonded at any ring carbon. In someembodiments, Ar₄ is selected from the group consisting of pyridinyl,pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, Ar₄ is2-pyridyl. In some embodiments, D is CR₂R₃, R₂ is Formula (C), G isCR₁₆R₁₇ and R₁₆ and R₁₇ are independently H or C₁₋₂ alkyl.

In some embodiments, D is CR₂R₃, R₂ is Formula (C) and G is S, S(O) orS(O)₂.

In some embodiments, Ar₄ is phenyl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro.

In some embodiments, Ar₄ is phenyl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, halogen and hydroxyl.

In some embodiments, Ar₄ is phenyl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl, halogen andhydroxyl.

In some embodiments, Ar₄ is heteroaryl optionally substituted with 1 to5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₄-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro.

In some embodiments, Ar₄ is heteroaryl optionally substituted with 1 to5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, halogen and hydroxyl.

In some embodiments, Ar₄ is heteroaryl optionally substituted with 1 to5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl, halogen andhydroxyl. In some embodiments, Ar₄ is a 5-membered heteroaryl, forexample, as shown in TABLE 2A, supra.

In some embodiments, Ar₄ is a 6-membered heteroaryl, for example, asshown in TABLE 4, supra.

In some embodiments, Ar₄ is selected from the group consisting ofpyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments,Ar₄ is 2-pyridyl.

In some embodiments, R₃ is H.

In some embodiments, D is N—R₂. In some embodiments, R₂ is selected fromthe group consisting of H, C₁₋₅ acyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,C₁₋₄ alkylsulfonyl, carbo-C₁₋₆-alkoxy, carboxamide, C₃₋₆-cycloalkyl andC₁₋₄ haloalkyl. In some embodiments, R₂ is selected from the groupconsisting of C(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂,C(O)CH₂CH₂CH₂CH₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃),CH₂(CH₂)₂CH₃, CH₂(CH₂)₃CH₃, C(O)NHCH₃, C(O)NHCH₂CH₃, C(O)NHCH₂CH₂CH₃,C(O)NHCH(CH₃)₂, C(O)NHCH₂(CH₂)₂CH₃, CO₂CH₃, CO₂CH₂CH₃, CO₂CH₂CH₂CH₃,CO₂CH(CH₃)₂ and CO₂CH₂(CH₂)₂CH₃. In some embodiments, R₂ is selectedfrom the group consisting of S(O)₂CH₃, S(O)₂CH₂CH₃, S(O)₂CH₂CH₂CH₃,S(O)₂CH(CH₃)₂, S(O)₂CH₂(CH₂)₂CH₃, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, CH₂CF₃, CF₃ and CHF₂.

In some embodiments, D is N—R₂ and R₂ is H, or carbo-C₁₋₆-alkoxy. Insome embodiments, R₂ is selected from the group consisting of CO₂CH₃,CO₂CH₂CH₃, CO₂CH₂CH₂CH₃, CO₂CH(CH₃)₂ and CO₂CH₂(CH₂)₂CH₃. In someembodiments, R₂ is C₁₋₈ alkyl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₄ alkylsulfonyl,carbo-C₁₋₆-alkoxy, and carboxy. In some embodiments, R₂ is CH₂CO₂Et, orCH₂CH₂CO₂H. In some embodiments, R₂ is selected from the groupconsisting of CH₂CH₂S(O)₂CH₃, CH₂CH₂S(O)₂CH₂CH₃, CH₂CH₂S(O)₂CH₂CH₂CH₃,CH₂CH₂S(O)₂CH(CH₃)₂ and CH₂CH₂S(O)₂CH₂(CH₂)₂CH₃.

In some embodiments, D is N—R₂ wherein R₂ is C₁₋₈ alkyl, heteroaryl orphenyl optionally substituted with 1 to 5 substituents selected from thegroup consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro. In some embodiments, R₂ is selected from thegroup consisting of CH₂CH₂OCH₃, CH₂CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₂CH₃,CH₂CO₂H, CH₂CH₂CO₂H, CH₂CH₂OH and CH₂CH₂CH₂OH. In some embodiments, R₂is selected from the group consisting of CH₂CH₂SCH₃, CH₂CH₂SCH₂CH₃,CH₂CH₂SCH₂CH₂CH₃, CH₂CH₂SCH(CH₃)₂, CH₂CH₂SCH₂(CH₂)₂CH₃, CH₂CH₂S(O)CH₃,CH₂CH₂S(O)CH₂CH₃, CH₂CH₂S(O)CH₂CH₂CH₃, CH₂CH₂S(O)CH(CH₃)₂,CH₂CH₂S(O)CH₂(CH₂)₂CH₃, CH₂CH₂S(O)₂CH₃, CH₂CH₂S(O)₂CH₂CH₃,CH₂CH₂S(O)₂CH₂CH₂CH₃, CH₂CH₂S(O)₂CH(CH₃)₂ and CH₂CH₂S(O)₂CH₂(CH₂)₂CH₃.In some embodiments, R₂ is selected from the group consisting of1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,4-triazol-5-yl and 1,2,4-triazol-1-yl,3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,3-ethyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl,5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl,3-methyl-1,2,4-triazol-5-yl, 3-ethyl-1,2,4-triazol-5-yl,3-methyl-1,2,4-triazol-1-yl, 3-ethyl-1,2,4-triazol-1-yl,5-methyl-1,2,4-triazol-1-yl and 5-ethyl-1,2,4-triazol-1-yl.

In some embodiments, D is N—R₂ and R₂ is —Ar₂-Ar₃ wherein Ar₂ and Ar₃are independently aryl or heteroaryl optionally substituted with 1 to 5substituents selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, halogen, hydroxyl and nitro. In some embodiments, compoundsof the present invention are represented by Formula (It) as shown below:

wherein each variable in Formula (It) has the same meaning as describedherein. In some embodiments, Ar₂ is a heteroaryl and Ar₃ is phenyl. Insome embodiments, the heteroaryl and phenyl are optionally substitutedwith 1 to 5 substituents selected from the group consisting of H, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen,hydroxyl and nitro.

In some embodiments, D is N—R₂ wherein R₂ is Formula (C):

wherein:

G is C═O or CR₁₆R₁₇; where R₁₆ and R₁₇ are independently H or C₁₋₈alkyl; and Ar₄ is phenyl or heteroaryl optionally substituted with 1 to5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments,compounds of the present invention are represented by Formula (Iu) asshown below:

wherein each variable in Formula (Iu) has the same meaning as describedherein.

In some embodiments, D is N—R₂, R₂ is Formula (C) and G is C═O. In someembodiments, Ar₄ is phenyl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments, Ar₄is phenyl optionally substituted with 1 to 5 substituents selected fromthe group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl. In some embodiments, Ar₄ is phenyloptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkyl, halogen and hydroxyl. In some embodiments, Ar₄ isheteroaryl optionally substituted with 1 to 5 substituents selected fromthe group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments, Ar₄is heteroaryl optionally substituted with 1 to 5 substituents selectedfrom the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl. In some embodiments, Ar₄ is heteroaryloptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkyl, halogen and hydroxyl. In some embodiments, Ar₄ is a5-membered heteroaryl, for example, as shown in TABLE 2A, supra. In someembodiments, Ar₄ is a 6-membered heteroaryl, for example, as shown inTABLE 4, supra. In some embodiments, Ar₄ is selected from the groupconsisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In someembodiments, Ar₄ is 2-pyridyl.

In some embodiments, D is N—R₂ wherein R₂ is Formula (C) and G isCR₁₆R₁₇. In some embodiments, Ar₄ is phenyl optionally substituted with1 to 5 substituents selected from the group consisting of C₁₋₅ acyl,C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments, Ar₄is phenyl optionally substituted with 1 to 5 substituents selected fromthe group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl. In some embodiments, Ar₄ is phenyloptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkyl, halogen and hydroxyl. In some embodiments, Ar₄ isheteroaryl optionally substituted with 1 to 5 substituents selected fromthe group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₆ dialkylcarboxamide, C₁₋₄dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments, Ar₄is heteroaryl optionally substituted with 1 to 5 substituents selectedfrom the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl. In some embodiments, Ar₄ is heteroaryloptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkyl, halogen and hydroxyl. In some embodiments, Ar₄ is a5-membered heteroaryl, for example, as shown in TABLE 2A, supra. In someembodiments, Ar₄ is a 6-membered heteroaryl, for example, as shown inTABLE 4, supra. In some embodiments, Ar₄ is selected from the groupconsisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In someembodiments, Ar₄ is 2-pyridyl. In some embodiments, D is N—R₂ wherein R₂is Formula (C), G is C₁₆R₁₇ and R₁₆ and R₁₇ are independently H or C₁₋₂alkyl.

In some embodiments, Z is selected from the group consisting of C₁₋₅acyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, amino, cyano, C₄₋₈ diacylamino,C₂₋₆ dialkylsulfonamide, formyl, halogen, heterocyclic, and nitrowherein C₁₋₈ alkyl and C₁₋₅ acyl are each optionally substituted with 1,or 2 groups selected from the group consisting of C₂₋₄ dialkylamino,hydroxy, and halogen.

In some embodiments, Z is selected from the group consisting of nitro,amino, formyl, NHC(O)CF₃, Br, NHC(O)CH₃, N(C(O)CH₃)₂, N(S(O)₂CH₃)₂, CH₃,[1,3]dioxolan-2-yl, CH₂OH, CH₂N(CH₃)₂, and C(O)CH₃.

In some embodiments, Z is selected from the group consisting of C₁₋₅acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,carboxamide, carboxy, cyano, aryl, C₁₋₄ haloalkyl, C₁₋₄haloalkylcarboxamide, heteroaryl, hydroxyl, hydroxylamino, nitro andtetrazolyl, wherein C₁₋₈ alkyl is optionally substituted with 1, 2, 3 or4 groups selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy,C₁₋₄ alkoxy, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, formyl, C₁₋₄haloalkoxy, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro.

In some embodiments, Z is selected from the group consisting of C₁₋₅acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, carboxamide,carboxy, cyano, aryl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide,heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl.

In some embodiments, Z is a heterocyclic group. In some embodiments, Zis a 5-membered heterocyclic group containing two oxygen atoms.

In some embodiments, Z is an alkyl group optionally substitutedC₂₋₄-dialkylamino or hydroxy.

In some embodiments, Z is selected from the group consisting of formyl,NHC(O)CH₃, NHC(O)CH₂CH₃, NHC(O)CH(CH₃)₂, CH₃, CH₂CH₃, CH(CH₃)₂,CH₂CH₂CH₂CH₃, NHC(O)CF₃, carboxy, CF₃, CF₂CF₃, nitro and1H-tetrazol-5-yl.

In some embodiments, Z is selected from the group consisting of carboxy,CF₃, nitro and 1H-tetrazol-5-yl.

In some embodiments, Z is [1,3]-dioxolan-2-yl.

In some embodiments, Z is a formyl group.

In some embodiments, Z is a carboxy group.

In some embodiments, Z is a —CH₂OH group.

In some embodiments, Z is a —CH₂N(CH₃)₂ group.

In some embodiments, Z is Formula (A):

wherein:

R₇ is H, C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₈ is H, nitro or nitrile.In some embodiments, R₇ is H or C₁₋₈ alkyl.

In some embodiments, R₁ is selected from the group consisting of H, C₁₋₄alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, amino, C₃₋₆ cycloalkyl and C₁₋₄haloalkyl. In some embodiments, R₁ is H or amino.

In some embodiments, R₁ is selected from the group consisting of H, C₁₋₈alkyl, and amino.

In some embodiments, Ar₁ is aryl optionally substituted with R₉-R₁₃. Insome embodiments, Ar₁ is phenyl.

In some embodiments, Ar₁ is heteroaryl. In some embodiments, Ar₁ isheteroaryl optionally substituted with R₉-R₁₃. In some embodiments, Ar₁is a heteroaryl selected from TABLE 2A. In some embodiments, Ar₁ is aheteroaryl selected from TABLE 4 or an N-oxide thereof. In someembodiments, compounds of the invention are of Formula (Iv):

wherein A, B, D, V, W, X, Y, Z, R₁, R₉, R₁₀, R₁₁ and R₁₂ have the samemeaning as described herein, supra and infra.

In some embodiments, Ar₁ is heteroaryl and R₉ is selected from the groupconsisting of H, C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide andsulfonamide.

In some embodiments, R₉ is selected from the group consisting of C₁₋₅acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, arylsulfonyl, C₂₋₆ dialkylamino,C₂₋₆ dialkylsulfonamide, and carboxamide.

In some embodiments, R₉ is selected from the group consisting ofC(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂CH₂CH₂CH₃,OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, CH₂(CH₂)₃CH₃,CH₂(CH₂)₄CH₃, CH₂(CH₂)₅CH₃, C(O)NHCH₃, C(O)NHCH₂CH₃, C(O)NHCH₂CH₂CH₃,C(O)NHCH(CH₃)₂, S(O)₂NHCH₃, S(O)₂NHCH₂CH₃, S(O)₂NHCH₂CH₂CH₃,S(O)₂NHCH(CH₃)₂, S(O)₂NHCH₂(CH₂)₂CH₃, S(O)₂NHCH(CH₃)CH₂CH₃,S(O)₂N(CH₃)₂, S(O)₂N(Et)(CH₃), S(O)₂CH₃, S(O)₂CH₂CH₃, S(O)₂CH₂CH₂CH₃,S(O)₂CH(CH₃)₂, S(O)₂CH₂(CH₂)₂CH₃, S(O)₂CH(CH₃)CH₂CH₃, SCH₃, SCH₂CH₃,SCH₂CH₂CH₃, SCH(CH₃)₂, SCH₂(CH₂)₂CH₃, amino, S(O)₂Ph, N(CH₃)₂,N(CH₃)(Et), N(Et)₂ and C(O)NH₂.

In some embodiments, R₉ is selected from the group consisting of cyano,C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfonyl, and C₁₋₄ haloalkylthio.

In some embodiments, R₉ is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cl, F, Br, OCF₃,OCHF₂, OCH₂CF₃, CF₃, CHF₂, CH₂CF₃, SCF₃, SCHF₂ and SCH₂CF₃.

In some embodiments, R₉ is selected from the group consisting of CN,CO₂Me, CO₂Et, S(O)₂CH₃, S(O)₂CF₃, N(CH₃)₂, N(Et)₂, C(O)NHCH₃, C(O)NHEt,C(O)N(CH₃)₂, OH, OCH₃, and OEt.

In some embodiments, R₉ is selected from the group consisting ofheterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxy, C₄₋₇oxo-cycloalkyl, phenoxy and phenyl.

In some embodiments, R₉ is selected from the group consisting of C₁₋₅acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carboxamide, halogen and sulfonamide.

In some embodiments, R₉ is selected from the group consisting ofC(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂CH₂CH₂CH₃,OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, CH₂(CH₂)₃CH₃,CH₂(CH₂)₄CH₃, CH₂(CH₂)₅CH₃, C(O)NHCH₃, C(O)NHCH₂CH₃, C(O)NHCH₂CH₂CH₃,C(O)NHCH(CH₃)₂, C(O)NHCH₂(CH₂)₂CH₃, CCH, S(O)₂NHCH₃, S(O)₂NHCH₂CH₃,S(O)₂NHCH₂CH₂CH₃, S(O)₂NHCH(CH₃)₂, S(O)₂NHCH₂(CH₂)₂CH₃,S(O)₂NHCH(CH₃)CH₂CH₃, S(O)CH₃, S(O)CH₂CH₃, S(O)CH₂CH₂CH₃, S(O)CH(CH₃)₂,S(O)CH₂(CH₂)₂CH₃, S(O)CH(CH₃)CH₂CH₃, S(O)₂CH₃, S(O)₂CH₂CH₃,S(O)₂CH₂CH₂CH₃, S(O)₂CH(CH₃)₂, S(O)₂CH₂(CH₂)₂CH₃, S(O)₂CH(CH₃)CH₂CH₃,SCH₃, SCH₂CH₃, SCH₂CH₂CH₃, SCH(CH₃)₂ and SCH₂(CH₂)₂CH₃.

In some embodiments, R₉ is selected from the group consisting of amino,arylsulfonyl, carboxy, cyano, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl and C₁₋₄ haloalkylthio.

In some embodiments, R₉ is selected from the group consisting ofphenylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cl, F,Br, OCF₃, OCHF₂, OCH₂CF₃, CF₃, CHF₂, CH₂CF₃, SCF₃, SCHF₂ and SCH₂CF₃.

In some embodiments, R₉ is selected from the group consisting ofheterocyclic, heteroaryl, C₄₋₇ oxo-cycloalkyl, phenoxy and phenyl. Insome embodiments, R₉ is selected from the group consisting ofmorpholin-4-yl, thiomorpholin-4-yl, 1-oxo-1λ⁴-thiomorpholin-4-yl,1,1-Dioxo-1λ⁶-thiomorpholin-4-yl, 4-methyl-piperazin-1-yl,4-ethyl-piperazin-1-yl, 4-propyl-piperazin-1-yl, piperidin-1-yl,pyrrolidin-1-yl, 2,5-dioxo-imidazolidin-4-yl,2,4-dioxo-thiazolidin-5-yl, 4-oxo-2-thioxo-thiazolidin-5-yl,3-methyl-2,5-dioxo-imidazolidin-4-yl,3-methyl-2,4-dioxo-thiazolidin-5-yl,3-methyl-4-oxo-2-thioxo-thiazolidin-5-yl,3-ethyl-2,5-dioxo-imidazolidin-4-yl, 3-ethyl-2,4-dioxo-thiazolidin-5-yl,and 3-ethyl-4-oxo-2-thioxo-thiazolidin-5-yl.

In some embodiments, R₉ is selected from the group consisting of1H-imidazol-4-yl, [1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl,[1,2,4]triazol-4-yl, pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl,imidazol-1-yl, oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl,[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl,tetrazol-1-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl,1,3-dioxo-1,3-dihydro-isoindol-2-yl and [1,2,3]thiadiazol-4-yl.

In some embodiments, R₉ is C₁₋₈ alkyl or C₁₋₄ alkoxy optionallysubstituted with 1 to 5 substituents selected independently from thegroup consisting of C₁₋₄ alkoxy, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, heterocyclic,hydroxyl and phenyl.

In some embodiments, R₉ is C₁₋₄ alkylsulfonyl optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₄ alkoxy, carboxamide, heteroaryl, heterocyclic andphenyl.

In some embodiments, R₉ is C₁₋₄ alkylsulfonyl substituted with theheteroaryl group. In some embodiments, the heteroaryl is selected fromthe group consisting of 1H-imidazol-4-yl, [1,2,4]triazol-1-yl,[1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl, pyrrol-1-yl, pyrazol-1-yl,1H-pyrazol-3-yl, imidazol-1-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl,[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl,tetrazol-1-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl,1,3-dioxo-1,3-dihydro-isoindol-2-yl and [1,2,3]thiadiazol-4-yl.

In some embodiments, R₉ is arylsulfonyl, heteroaryl, phenoxy or phenyloptionally substituted with 1 to 5 substituents selected independentlyfrom the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carboxamide, carboxy, cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio and hydroxyl.

In some embodiments, R₉ is arylsulfonyl, heteroaryl, phenoxy or phenyleach optionally substituted with 1 to 5 substituents selectedindependently from the group consisting of C₁₋₄ alkoxy, C₁₋₈ alkyl,cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl.

In some embodiments, R₉ is a heterocyclic group as described herein.

In some embodiments, R₉ is a heterocyclic group represented by theformulae shown in Table 2B, supra. In some embodiments, R₉ is aheterocyclic group represented by the formulae shown in Table 2C, supra.In some embodiments, R₉ is a heterocyclic group represented by theformulae shown in Table 2D, supra. In some embodiments, R₉ is aheterocyclic group represented by the formulae shown in Table 2E, supra.In some embodiments, R₉ is a heterocyclic group represented by theformulae shown in Table 2F, supra. In some embodiments, R₉ is aheterocyclic group represented by the formulae shown in Table 2G, supra.

In some embodiments, R₉ is of Formula (D):

wherein:

“p” and “r” are independently 0, 1, 2 or 3; and R₁₈ is H, C₁₋₅ acyl,C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl or phenyl, andwherein the heteroaryl or phenyl may be optionally substituted with 1 to5 substituents selected independently from the group consisting of C₁₋₄alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl.

In some embodiments, R₉ is of Formula (D) wherein “p” and “r” areindependently 0, or 1; and R₁₈ is H, carbo-C₁₋₆-alkoxy, heteroaryl orphenyl, and wherein the heteroaryl and phenyl are each optionallysubstituted with 1 to 5 substituents selected independently from thegroup consisting of C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl,C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl andhydroxyl.

In some embodiments, p=0 and r=0.

In some embodiments, R₁₈ is phenyl optionally substituted with 1 to 5substituents selected independently from the group consisting of C₁₋₄alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl.

In some embodiments, p=0 and r=1.

In some embodiments, R₁₈ is carbo-C₁₋₆-alkoxy or carboxy.

In some embodiments, p=0 and r=0.

In some embodiments, R₁₈ is heteroaryl or phenyl optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl. Insome embodiments, the heteroaryl is selected from the group consistingof 1H-imidazol-4-yl, [1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl,[1,2,4]triazol-4-yl, pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl,imidazol-1-yl, oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl,[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl,tetrazol-1-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl,1,3-dioxo-1,3-dihydro-isoindol-2-yl and [1,2,3]thiadiazol-4-yl.

In some embodiments, p=2 and r=1. In some embodiments, R₁₈ is H, C₁₋₅acyl or C₁₋₈ alkyl.

In some embodiments, R₁₀-R₁₃ are independently C₁₋₅ acyl, C₁₋₄ alkoxy,C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxyand C₁₋₄ haloalkyl.

In some embodiments, one or two R₁₀-R₁₃ groups are independentlyhalogen. In some embodiments, one R₁₀-R₁₃ group is a halogen.

In some embodiments, Ar₁ is phenyl and R₉ is substituted at the paraposition on the phenyl.

In some embodiments, Ar₁ is phenyl optionally substituted with R₉, R₁₀and R₁₁. In some embodiments, the compounds of the invention are ofFormula (Iw):

wherein A, B, D, V, W, X, Y, Z, R₁ have the same meaning as describedherein, supra and infra, and R₉ is cyano, carbo-C₁₋₆-alkoxy, carboxy,C₂₋₆ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄alkylsulfonyl, hydroxyl, C₁₋₄ alkoxy, 5-membered heteroaryl, 6-memberedheteroaryl, or heterocyclic, wherein the 6-membered heteroaryl isoptionally an N-oxide; and R₁₀ and R₁₁ are independently H or halogen.In some embodiments, R₉ is cyano, carbomethoxy, carboethoxy,carboisopropoxy, carboxy, dimethylamino, diethylamino, methylethylamino,C(O)NHCH₃, C(O)NHCH₂CH₃, C(O)NH(CH₃)₂, S(O)₂CH₃, S(O)₂CH₂CH₃, hydroxyl,OCH₃, [1,2,4]triazol-4-yl, thiazol-2-yl, 3H-imidazol-4-yl,1H-imidazol-2-yl, 1H-imidazol-4-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl,1-oxy-pyridin-4-yl, or 2-oxo-oxazolidin-4-yl. In some embodiments, R₁₀is H and R₁₁ is F.

In some embodiments, Ar₁ is phenyl and two adjacent R₁₀-R₁₁ groups forma 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclic group withthe phenyl group wherein the 5, 6 or 7 membered group is optionallysubstituted with halogen.

In some embodiments, Ar₁ is phenyl and two adjacent R₁₀-R₁₁ groups forma 5, 6 or 7 membered cycloalkyl group with the phenyl group and is ofthe formulae shown below:

TABLE 5

wherein “a” is 1, 2 or 3 to give a 5, 6 or 7 membered cycloalkyl fusedtogether with the phenyl group where two of the ring carbons are sharedbetween the cycloalkyl and phenyl group. In some embodiments, thecycloalkyl is optionally substituted with halogen. In some embodiments,the halogen is fluorine.In some embodiments, Ar₁ is phenyl and two adjacent R₁₀-R₁₁ groups forma 5, 6 or 7 membered cycloalkenyl group with the phenyl group and is ofthe formulae shown in TABLE 5 and has at least one carbon-carbon ringdouble bond present that is not part of the phenyl group (i.e.,cycloalkenyl), for example, 1H-Indenyl and dihydro-naphthyl. In someembodiments, the cycloalkenyl is optionally substituted with halogen. Insome embodiments, the halogen is fluorine.

In some embodiments, Ar₁ is phenyl and two adjacent R₁₀-R₁₁ groups forma 5, 6 or 7 heterocyclic group with the phenyl group and is of theformulae in TABLE 5 wherein one or more ring cycloalkyl carbons arereplaced by a O, S, S(O), S(O)₂, NH or N—C₁₋₄-alkyl group. In someembodiments, the heterocyclic group is optionally substituted withhalogen. In some embodiments, the halogen is fluorine.

In some embodiments, Ar₁ is phenyl and two adjacent R₁₀-R₁₁ groups forma 5 membered heterocyclic group with the phenyl group. In someembodiments, the 5 membered heterocyclic group with the phenyl grouptogether form a 2,3-dihydro-benzofuran-5-yl or benzo[1,3]dioxol-5-ylgroup. In some embodiments, the two adjacent groups form a 6 memberedheterocyclic group with the phenyl group. In some embodiments, the 6membered heterocyclic group with the phenyl group together form a2,3-dihydro-benzo[1,4]dioxin-6-yl or 2,3-dihydro-benzo[1,4]dioxin-2-ylgroup. In some embodiments, the two adjacent groups form a 7 memberedheterocyclic group with the phenyl group. In some embodiments, the 7membered heterocyclic group with the phenyl group together form a3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl group.

In some embodiments, Ar₁ is heteroaryl and two adjacent R₁₀-R₁₁ groupsform a 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclic groupwith the heteroaryl group wherein the 5, 6 or 7 membered group isoptionally substituted with halogen. In some embodiments, Ar₁ is aheteroaryl selected from TABLE 2A. In some embodiments, Ar₁ is aheteroaryl selected from TABLE 4. In some embodiments, the two adjacentgroups form a 5 membered heterocyclic group with the heteroaryl group.In some embodiments, the two adjacent groups form a 6 memberedheterocyclic group with the heteroaryl group. In some embodiments, thetwo adjacent groups form a 7 membered heterocyclic group with theheteroaryl group.

In some embodiments, R₅ is H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl,C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, arylsulfonyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, hydroxyl, nitro,C₄₋₇ oxo-cycloalkyl, sulfonamide and nitro.

In some embodiments, R₅ and R₆ are independently H or F.

In some embodiments, X is N and Y is CH.

In some embodiments, X is N and Y is CF.

In some embodiments, X is CH and Y is N.

In some embodiments, X and Y are N.

In some embodiments, X and Y are CH.

In some embodiments, X is CH and Y is CF.

Some embodiments of the present invention include compounds illustratedin TABLES A, B, C, D and E; these TABLES are shown below.

TABLE A Cmpd# Structure Chemical Name A1

1-[6-(4-Imidazol-1-yl-phenoxy)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A2

1-[6-(2-Methyl-5-trifluoromethyl- 2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A3

1-[6-(4-Methanesulfonyl-phenoxy)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A4

1-[6-(Benzo[1,2,5]oxadiazol-5- yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A5

1-{6-[4-(2-Methoxycarbonyl-acetyl)- phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A6

1-[5-Amino-6-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A7

1-[6-(2-Methyl-5-trifluoromethyl- 2H-pyrazol-3-yloxy)-5-(2,2,2-trifluoro-acetylamino)-pyrimidin- 4-yl]-piperidine-4-carboxylic acidethyl ester A8

Propionic acid 1-[2-amino-5-formyl- 6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]- piperidin-4-yl ester A9

4-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4- yl]-piperazine-1-carboxylic acidethyl ester A10

1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4- yl]-piperidine-4-carboxylic acidmethyl ester A11

2,6-Dimethyl-4-[6-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-morpholine A12

1-[6-(2-Methyl-5-trifluoromethyl-2H- pyrazol-3-yloxy-5-nitro-pyrimidin-4-yl]-piperidine-3-carboxylic acid ethyl ester A13

1-[6-(2-Methyl-5-trifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethylamide A14

1-[6-(2-Methyl-5-phenyl-2H-pyrazol- 3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A15

4-(2-Methyl-5-trifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro-6-piperidin-1-yl-pyrimidine A16

1-[5-Nitro-6-(2-trifluoromethyl- benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A17

1-[5-Nitro-6-(3-trifluoromethyl- benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A18

1-[5-Nitro-6-(4-trifluoromethyl- benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A19

1-[5-Bromo-6-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A20

1-[5-Acetylamino-6-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A21

1-[5-Diacetylamino-6-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A22

1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4- yl]-piperidine-4-carboxylic acidA23

1-{5-Nitro-6-[2-(2-trifluoromethyl- phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A24

1-{5-Nitro-6-[2-(3-trifluoromethyl- phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A25

1-[5-Di-(methanesulfonyl)amino-6- (2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethylester A26

1-[5-Nitro-6-(3-trifluoromethyl- phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A27

1-[5-Methyl-6-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A28

1-[5-Nitro-6-(2-trifluoromethyl- phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A29

1-[5-Nitro-6-(4-trifluoromethyl- phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A30

1-[6-(4-Fluoro-phenoxy)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A31

1-[6-(2,5-Dimethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A32

1-[6-(4-Bromo-phenoxy)-5-nitro- pyrimidin-4-yl]-piperidine-4- carboxylicacid ethyl ester A33

1-[6-(4-Chloro-phenoxy)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A34

1-[6-(4-Carbamoyl-phenoxy)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A35

1-{6-[4-(2-Methoxy-ethyl)-phenoxy]- 5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A36

1-[6-(4-Cyclopentyl-phenoxy)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A37

1-[5-Nitro-6-(4-pyrrol-1-yl-phenoxy)- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A38

1-[6-(4-Benzoyl-phenoxy)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A39

1-{6-[4-(4-Hydroxy- benzenesulfonyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester A40

1-[6-(4′-Cyano-biphenyl-4-yloxy)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A41

1-[6-(2-Amino-4-ethanesulfonyl- phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A42

1-{6-[4-(5-Hydroxy-pyrimidin-2- yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A43

1-[5-Nitro-6-(4-sulfo-phenoxy)- pyrimidin-4-yl]-piperidine-4- carboxylicacid ethyl ester A44

1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine- 4-carboxylic acid ethyl ester A45

1-[6-(4-Carbamoylmethyl-phenoxy)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A46

1-{6-[4-(1,3-Dioxo-1,3-dihydro- isoindol-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester A47

1-[6-(4′-Methoxy-biphenyl-4- yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A48

1-{6-[4-(2,5-Dioxo-imidazolidin- 4-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester A49

4-(4,4-Difluoro-piperidin-1-yl)- 6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro- pyrimidine A50

1-{5-Nitro-6-[4-(4-oxo- cyclohexyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A51

1-{5-Nitro-6-[4-(3-oxo-butyl)- phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A52

1-[5-Nitro-6-(4-propionyl- phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A53

1-[5-Nitro-6-(4-[1,2,3]thiadiazol- 4-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A54

1-{6-[4-(2-Hydroxy-ethyl)- phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A55

{4-[6-(4,4-Difluoro-piperidin-1- yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone A56

3-{4-[6-(4,4-Difluoro-piperidin- 1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionic acid methyl ester A57

2-[6-(4,4-Difluoro-piperidin-1- yl)-5-nitro-pyrimidin-4-yloxy]-5-ethanesulfonyl-phenylamine A58

4-(4-Cyclopentyl-phenoxy)-6- (4,4-difluoro-piperidin-1-yl)-5-nitro-pyrimidine A59

1-[6-(2,6-Dichloro-4- methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine- 4-carboxylic acid ethyl ester A60

1-{6-[4-(4-Chloro-benzoyl)- phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A61

1-{6-[4-(4-Hydroxy-benzoyl)- phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A62

1-[6-(4-Cyanomethyl-phenoxy)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A63

(4-{6-[4-(2-Methanesulfonyl- ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)- phenyl-methanone A64

4-(4-{6-[4-(2-Methanesulfonyl- ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)- butan-2-one A65

3-(4-{6-[4-(2-Methanesulfonyl- ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-3- oxo-propionic acid methyl ester A66

4-(4-Methyl-piperidin-1-yl)-6-(2- methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro pyrimidine A67

4-(4-Bromo-piperidin-1-yl)-6-(2- methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine A68

4-(2-Methyl-5-trifluoromethyl- 2H-pyrazol-3-yloxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine A69

1-[6-(2-Methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]- piperidine-4-carboxylic acid amide A70

1-[5-Nitro-6-(2-oxo-2H- chromen-6-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A71

1-[5-Nitro-6-(2-oxo- benzo[1,3]oxathiol-6-yloxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A72

1-[6-(9H-Carbazol-2-yloxy)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A73

1-[5-Nitro-6-(9-oxo-9H-fluoren- 2-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A74

1-{5-Amino-6-[4-(3-oxo-butyl)- phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A75

1-[6-[4-(3-Oxo-butyl)-phenoxy]- 5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A76

1-{5-Amino-6-[4-(hydroxy- phenyl-methyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester A77

1-[6-(2-Benzoyl-5-methoxy- phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A78

1-[6-(6-Chloro-pyridin-3-yloxy)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A79

1-[6-(Benzo[1,3]dioxol-5-yloxy)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A80

1-[6-(4-Benzyloxy-phenoxy)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A81

1-[6-(3-Morpholin-4-yl- phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A82

1-[5-Nitro-6-(4- trifluoromethylsulfanyl- phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A83

1-[5-Nitro-6-(4- trifluoromethoxy-phenoxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A84

1-[6-(4-Benzoyl-phenoxy)-5- (2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A85

{4-[5-Nitro-6-(4-propyl- piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-phenyl- methanone A86

{4-Methoxy-2-[5-nitro-6-(4- propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-phenyl- methanone A87

4-{4-[5-Nitro-6-(4-propyl- piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2-one A88

5-Nitro-4-(4-propyl-piperidin-1- yl)-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine A89

3-{4-[5-Nitro-6-(4-propyl- piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionic acid methyl ester A90

5-Ethanesulfonyl-2-[5-nitro-6-(4- propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenylamine A91

4-[4-(3-Isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl- phenoxy)-pyrimidine-5- carbonitrile A92

1-[6-(4-Difluoromethoxy- benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A93

1-[6-(3-Difluoromethoxy- benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A94

2-{1-[6-(2-Methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]- piperidin-4-yl}-ethanol A95

3-{1-[6-(2-Methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]- piperidin-4-yl}-propionic acid A96

4-[4-(4-Methyl-benzyl)- piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidine A97

4-(3-Methanesulfonyl-pyrrolidin- 1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidine A98

4-(2-Methyl-5-trifluoromethyl- 2H-pyrazol-3-yloxy)-5-nitro-6-[4-(2-trifluoromethyl-phenoxy)- piperidin-1-yl]-pyrimidine A99

4-(2-Methyl-5-trifluoromethyl- 2H-pyrazol-3-yloxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)- piperidin-1-yl]-pyrimidine A100

4′-(4-Benzoyl-phenoxy)-3′-nitro- 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester A101

3′-Nitro-4′-[4-(3-oxo-butyl)- phenoxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester A102

4′-[4-(2-Methoxycarbonyl- acetyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl- 4-carboxylic acid ethyl ester A103

4′-(2-Amino-4-ethanesulfonyl- phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl- 4-carboxylic acid ethyl ester A104

4′-(4-Imidazol-1-yl-phenoxy)-3′- nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester A105

4-(2-Methyl-5-trifluoromethyl- 2H-pyrazol-3-yloxy)-5-nitro-6-(4-trifluoromethyl-piperidin-1- yl)-pyrimidine A106

4-(2-Methyl-5-trifluoromethyl- 2H-pyrazol-3-yloxy)-5-nitro-6-(4-phenylsulfanyl-piperidin-1- yl)-pyrimidine A107

1-[6-(3-Ethynyl-phenoxy)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A108

1-[6-(4-Chloro-2-fluoro- phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A109

1-[6-(2,4-Difluoro-phenoxy)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A110

1-[6-(4-Bromo-2-fluoro- phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A111

4-(3-Ethynyl-phenoxy)-5-nitro-6- (4-propyl-piperidin-1-yl)-pyrimidineA112

4-(4-Chloro-2-fluoro-phenoxy)- 5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine A113

4-(2,4-Difluoro-phenoxy)-5- nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine A114

4-(4-Bromo-2-fluoro-phenoxy)- 5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine A115

3′-Nitro-2′-[4-(3-oxo-butyl)- phenoxy]-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid ethyl ester A116

4-[4-(3′-Nitro-4-propyl-3,4,5,6- tetrahydro-2H-[1,4′]bipyridinyl-2′-yloxy)-phenyl]-butan-2-one A117

2′-(4-Benzoyl-phenoxy)-3′-nitro- 3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid ethyl ester A118

4-(4-{5-Nitro-6-[4-(pyridin-2- ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)- butan-2-one A119

[4-(3′-Nitro-4-propyl-3,4,5,6- tetrahydro-2H-[1,4′]bipyridinyl-2′-yloxy)-phenyl]-phenyl- methanone A120

4-(4-{5-Nitro-6-[4-(2- trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidin-4- yloxy}-phenyl)-butan-2-one A121

4-(4-{6-[4-(3-Methyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}- phenyl)-butan-2-one A122

(4-{6-[4-(3-Methyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}- phenyl)-phenyl-methanone A123

1-{6-[4-(4-Fluoro-benzoyl)- phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester A124

(4-Fluoro-phenyl)-{4-[5-nitro-6- (4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}- methanone A125

4-[4-(3-Methyl-[1,2,4]oxadiazol- 5-yl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro- pyrimidine A126

4-(4-Methoxymethyl-piperidin-1- yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidine A127

4-{4-[6-(4-Methoxymethyl- piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}- butan-2-one A128

4-[4-(2-Methoxy-ethyl)- piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidine A129

4-{4-[6-(4-Ethoxymethyl- piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}- butan-2-one A130

4-(2,4-Difluoro-phenoxy)-5- nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine A131

(4-Methoxy-2-{5-nitro-6-[4- (pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}- phenyl)-phenyl-methanone A132

4-(2,4-Difluoro-phenoxy)-6-(4- ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidine A133

4-{4-[6-(4- Cyclopropylmethoxymethyl- piperidin-1-yl-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one A134

4-{4-[5-Nitro-6-(4- propoxymethyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}- butan-2-one A135

1-{4-[6-(4-Methoxymethyl- piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-ethanone A136

4-{4-[2-Nitro-3-(4-propyl- piperidin-1-yl)-phenoxy]- phenyl}-butan-2-oneA137

1-{4-[2-Nitro-3-(4-propyl-piperidin- 1-yl)-phenoxy]-phenyl}-ethanoneA138

{4-[2-Nitro-3-(4-propyl- piperidin-1-yl)-phenoxy]-phenyl}-phenyl-methanone A139

3-{4-[2-Nitro-3-(4-propyl- piperidin-1-yl)-phenoxy]-phenyl}-3-oxo-propionic acid methyl ester A140

4-{4-[6-(4-Butoxymethyl- piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}- butan-2-one A141

4-{4-[6-(4-Isobutoxymethyl- piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}- butan-2-one A142

(4-Fluoro-phenyl)-[4-(3′-nitro-4- propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-yloxy)- phenyl]-methanone A143

4-[4-(3′-Nitro-4-propyl-3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-4′-yloxy)-phenyl]-butan-2-one A144

3′-Nitro-4-propyl-4′-(4- [1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H- [1,2′]bipyridinyl A145

1-{2-Nitro-3-[4-(3-oxo-butyl)- phenoxy]-phenyl}-piperidine-4- carboxylicacid ethyl ester A146

1-[3-(4-Benzoyl-phenoxy)-2- nitro-phenyl]-piperidine-4- carboxylic acidethyl ester A147

{4-[6-(4-Ethoxy-piperidin-1-yl)-5- nitro-pyrimidin-4-yloxy]-phenyl}-(4-fluoro-phenyl)-methanone A148

1-[6-(2-Methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]- piperidin-4-ol A149

1-[6-(4-Acetyl-phenoxy)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester A150

(l-{6-[4-(4-Fluoro-benzoyl)- phenoxy]-5-nitro-pyrimidin-4-yl}-piperidin-4yl)-(4-fluoro- phenyl)-methanone A151

4-(4-{6-[4-(4-Fluoro-benzoyl)- piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)- butan-2-one A152

4-(4-Methanesulfonyl-phenoxy)- 5-nitro-6-[4-(pyridin-2-ylsulfanyl)-cyclohexyl]-pyrimidine A153

4-(4-Methanesulfonyl-phenoxy)- 5-nitro-6-[4-(pyridin-4-ylsulfanyl)-cyclohexyl]-pyrimidine A154

4-(4-Methanesulfonyl-phenoxy)- 5-nitro-6-(4-phenylsulfanyl-cyclohexyl)-pyrimidine A155

1-[5-Nitro-6-(4- trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester A156

5-[1,3]Dioxolan-2-yl-4-[4-(3- isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4- methanesulfonyl-phenoxy)- pyrimidine A157

4-[4-(3-Isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)- pyrimidine-5-carbaldehyde A158

5-[1,3]Dioxolan-2-yl-4-[4-(3- isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4- [1,2,3]thiadiazol-4-yl-phenoxy)- pyrimidine A159

4-[4-(3-Isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl- phenoxy)-pyrimidine-5- carbaldehydeA160

4-[4-(3-Isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl- phenoxy)-pyrimidine-5- carboxylicacid A161

[4-[4-(3-Isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl- phenoxy)-pyrimidin-5-yl]-methanolA162

[4-[4-(3-Isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl- phenoxy)-pyrimidin-5-ylmethyl]-dimethyl-amine A163

4-[4-(3-tert-Butyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl- pyridin-3-yloxy)-5-nitro- pyrimidine A164

4-[4-(3-Isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl- phenoxy)-2-methyl-pyrimidine- 5-carbonitrileA165

1-[4-[4-(3-Isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)- pyrimidin-5-yl]-ethanone

TABLE B Cmpd # Structure Chemical Name B1

1-{6-[(Benzo[1,3]dioxol-5-ylmethyl)- amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B2

1-[5-Nitro-6-(3,4,5-trimethoxy- benzylamino)-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B3

(5-Nitro-6-piperidin-1-yl-pyrimidin- 4-yl)-(3-trifluoromethyl-benzyl)-amine B4

1-[5-Nitro-6-(2-trifluoromethyl- benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B5

1-[5-Nitro-6-(4-trifluoromethyl- benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B6

1-[5-Nitro-6-(3-trifluoromethyl- benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B7

(5-Nitro-6-piperidin-1-yl-pyrimidin- 4-yl)-(2-trifluoromethyl-benzyl)-amine B8

(5-Nitro-6-piperidin-1-yl-pyrimidin- 4-yl)-(4-trifluoromethyl-benzyl)-amine B9

1-[5-Amino-6-(3-trifluoromethyl- benzylamino)-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester B10

1-[5-Amino-6-(4-trifluoromethyl- benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B11

1-[6-(4-Bromo-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B12

1-[5-Nitro-6-(4-trifluoromethyl- phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B13

1-[6-(Methyl-phenyl-amino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B14

1-[5-Nitro-6-(4-trifluoromethoxy- phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B15

1-[6-(4-Fluoro-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B16

1-[6-(3,5-Difluoro-phenylamino)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B17

1-[6-(3,5-Dichloro-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B18

1-[6-(Benzo[1,3]dioxol-5-ylamino)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B19

1-[6-(2-Bromo-4-trifluoromethoxy- phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B20

1-[6-(2-Fluoro-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B21

1-[6-(3-Fluoro-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B22

1-{6-[(2-Fluoro-phenyl)-methyl- amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B23

1-[6-(Ethyl-phenyl-amino)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B24

1-{6-[(4-Chloro-phenyl)-methyl- amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B25

1-[6-(4-Difluoromethyl-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester B26

1-{6-[(2,3-Dihydro-benzo[1,4]dioxin- 6-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester B27

1-{6-[(2,3-Dihydro-benzo[1,4]dioxin- 2-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester B28

1-{6-[(2,3-Dihydro-benzofuran-5- ylmethyl)-amino-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B29

1-{6-[(6-Fluoro-4H-benzo[1,3] dioxin-8-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine- 4-carboxylic acid ethyl ester B30

1-[6-(3,4-Dihydro-2H-benzo[b] [1,4]dioxepin-7-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester B31

1-{6-[4-{Morpholine-4-sulfonyl)- phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B32

1-[6-(2,2-Difluoro-benzo[1,3]dioxol- 4-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B33

1-[6-(2,2-Difluoro-benzo[1,3]dioxol- 5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B34

1-[6-(1,1-Dioxo-1H-1λ⁶-benzo[b] thiophen-6-ylamino)-5-nitro-pyrimidin-4-yl)-piperidine-4- carboxylic acid ethyl ester B35

1-{6-[(Furan-3-ylmethyl)-amino]-5- nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B36

1-{6-[2-(4-Methoxy-phenoxy)- ethylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B37

1-{6-[2-(5-Methoxy-1H-indol-3-yl)- ethylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B38

(3,4-Dihydro-2H-benzo[b][1,4] dioxepin-7-yl)-[5-nitro-6-(4-propyl-piperidin-l-yl)- pyrimidin-4-yl]-amine B39

(3-Fluoro-phenyl)-[5-nitro-6-(4- propyl-piperidin-l-yl)-pyrimidin-4-yl]-amine B40

(3-Methoxy-phenyl)-[5-nitro-6-(4- propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine B41

1-{6-[(3-Fluoro-phenyl)-methyl- amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B42

1-[6-(4-Benzoyl-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B43

1-{6-[4-(1,1-Dioxo-1λ⁶-thiomorpholin- 4-ylmethyl)-phenylamino]-5-nitro-pyrimidin-4-yl)-piperidine-4- carboxylic acid ethyl ester B44

1-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B45

1-[6-(4-Dimethylsulfamoyl- phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B46

1-[6-(3-Methoxy-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B47

1-[6-(2-Methoxy-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B48

1-[6-(3,5-Bis-trifluoromethyl- phenylamino)-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester B49

1-[6-(2,5-Dimethoxy-phenylamino)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B50

1-[6-(3,5-Dimethoxy-benzylamino)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B51

[5-Nitro-6-(4-propyl-piperidin-1-yl)- pyrimidin-4-yl]-(3,4,5-trimethoxy-benzyl)-amine B52

(3,5-Dimethoxy-benzyl)-[5-nitro-6- (4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine B53

(4-{5-Nitro-6-[4-(pyridin-2- ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-ylamino)-phenyl)-phenyl- methanone B54

(4-{5-Nitro-6-[4-(2-trifluoromethyl- phenoxy)-piperidin-1-yl]-pyrimidin-4-ylamino}-phenyl)-phenyl- methanone B55

1-[6-(4-Cyano-phenylamino)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B56

1-[6-{3,5-Dimethoxy-phenylamino)- 5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B57

1-[6-(4-sec-Butyl-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B58

1-[6-(4-Heptyl-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B59

2′-(4-Benzoyl-phenylamino)-3′- nitro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid ethyl ester B60

1-[5-Nitro-6-(3,4,5-trimethoxy- phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B61

1-[5-Nitro-6-(4-pentyl-phenylamino)- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B62

l-{6-[4-(3-Carboxy-propyl)- phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B63

1-{6-[4-(Cyano-phenyl-methyl)- phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B64

1-[6-(4-Cyclohexyl-phenylamino)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B65

1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl- phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B66

1-[5-Nitro-6-(4-trifluoromethane- sulfonyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B67

1-[5-Nitro-6-(4-[1,2,3]thiadiazol- 4-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B68

[6-(4-Ethoxymethyl-piperidin-1-yl)- 5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine B69

[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl- phenyl)-amine B70

{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-(4- [1,2,4]triazol-1-yl-phenyl)-amineB71

(2-F1uoro-phenyl)-{6-[4-(3-methyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine B72

(4-Methanesulfonyl-phenyl)-{6-[4-(3- methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin- 4-yl}-amine B73

{6-[4-(3-Methyl-[1,2,4]oxadiazol- 5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4)triazol- 1-yl-phenyl)-amine B74

1-{5-Nitro-6-[4-(4-trifluoromethyl- phenoxy)-phenylamino]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester B75

{6-[4-(3-Ethyl-(1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin- 4-yl}-(2-fluoro-phenyl)-amine B76

{6-[4-(2-Methoxy-phenylsulfanyl)- piperidin-1-yl)-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-y1- phenyl)-amine B77

(4-Methanesulfonyl-phenyl)-{5- nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4- yl}-amine B78

(3-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]- pyrimidin-4-yl}-amine B79

Benzo[1,3]dioxol-5-yl-[5-nitro-6-(4- propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine B80

(4-Fluoro-phenyl)-{1-[5-nitro-6-(4- [1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidin-4-yl}- methanone B81

[5-Nitro-6-(4-phenylsulfanyl- piperidin-1-yl)-pyrimidin-4-yl]-(4-(1,2,4]triazol-1-yl-phenyl)- amine B82

(4-Fluoro-phenyl)-{1-[6-(2-fluoro- phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone B83

1-[6-(2-Methyl-5-phenyl-2H- pyrazol-3-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester B84

(4-Methanesulfonyl-phenyl)-[5- nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]- amine B85

(4-Methanesulfonyl-phenyl)-{5- nitro-6-[4-(pyridin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}- amine B86

{6-[4-(4-Fluoro-phenoxy)- piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)- amine B87

(4-Methanesulfonyl-phenyl)-{5- nitro-6-[4-(pyridin-4-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}- amine B88

(4-Methanesulfonyl-phenyl)-{5- nitro-6-[4-(pyrimidin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}- amine B89

(4-Methanesulfbnyl-phenyl)-{5- nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}- amine B90

(4-Methanesulfonyl-phenyl)-{6- [4-(4-methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin- 4-yl}-amine B91

[6-(4-Benzenesulfonyl-piperidin- 1-yl)-5-nitro-pyrimidin-4-yl]-(4-mcthanesulfonyl-phenyl)-amine B92

{4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yl]-piperazin-l-yl}-acetic acid ethyl ester B93

(2-Fluoro-phenyl)-{5-nitro-6-[4- (pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine B94

2-Methoxy-phenyl)-{5-nitro-6-[4- (pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine B95

(4-Methanesulfonyl-phenyl)-(5- nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]- piperidin-1-yl}-pyrimidin-4-yl)- amineB96

{6-[4-(3-Ethyl-[1,2,4]oxadiazol- 5-yl)-piperidin-1-yl)-5-nitro-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amine B97

(6-{4-[5-(4-Fluoro-phenyl)- [1,3,4]oxadiazo]-2-yl]-piperidin-1-yl}-5-nitro-pyrimidin-4-yl)-(4- methanesulfonyl-phenyl)-amine B98

(4-Methanesulfonyl-phenyl)-[5- nitro-6-(4-pyridin-2-ylmethyl-piperidin-l-yl)-pyrimidin-4-yl]- amine B99

4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl- phenylamino)-pyrimidine-5- carbonitrile B100

1-{6-[4-(4,5-Dichloro-imidazol- 1-yl)-phenylamino)-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester B101

Benzo[1,3]dioxol-5-yl-{5-nitro-6- [4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}- amine B102

(4-Fluoro-phenyl)-{1-[6-(2- fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}- methanone B103

{1-[6-(Benzo[1,3]dioxol-5- ylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-(4-fluoro- phenyl)-methanone B104

(2,3-Difluoro-phenyl)-{5-nitro-6- [4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}- amine B105

(2,4-Difluoro-phenyl)-{5-nitro-6- [4-(pyridin-2-ylsulfanyl)-piperidin-l-yl]-pyrimidin-4-yl}- amine B106

(2,5-Difluoro-phenyl)-{5-nitro-6- [4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}- amine B107

1-[6-(4-Benzenesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester B108

1-[5-Nitro-6-{2-trifluoromethyl- 3H-benzoimidazol-5-ylamino)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester B109

l-{5-Nitro-6-[3-(1,1,2,2- tetrafluoro-ethoxy)-phenylamino]-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl esterB110

(6-[4-(4-Iodo-phenoxy)- piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl- phenyl)-amine B111

(2-Fluoro-4-methanesulfonyl- phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin- 1-yl]-5-nitro-pyrimidin-4-yl}- amineB112

{6-[4-(3-Ethyl-[1,2,4]oxadiazol- 5-yl)-piperidin-l-yl]-5-nitro-pyrimidin-4-yl-}-(2-fluoro-4- methanesulfonyl-phenyl)-amine B113

(4-Methanesulfonyl-phenyl)-{5- nitro-6-[4-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin- l-yl]-pyrimidin-4-yl}-amine B114

{6-[4-(3-Cyclopropylmethyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amine B115

{6-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl)-5-nitro-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amine B116

{6-[4-(3-Cyclopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amine B117

(4-Methanesulfonyl-phenyl)-(5- nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]- piperidin-l-yl}-pyrimidin-4-yl)- amineB118

4-[4-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-piperidin-1-yl]-6-(4-methanesulfinyl-phenylamino)- pyrimidine-5-carbonitrile B119

(4-Methanesulfonyl-phenyl)-{5- nitro-6-[4-(4-trifluoromethoxy-phenoxy)-piperidin-1-yl]- pyrimidin-4-yl}-amine B120

4-[4-(3-Isopropyl-[1,2,4) oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl- phenylamino)-pyrimidine-5- carbonitrile B121

1-{1-[6-(2-Fluoro-4- methancsulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4- yl}-hexan-1-one B122

1-{1-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one B123

{6-[4-(3-tert-Butyl-[1,2,4] oxadiazol-5-yl)-piperidin-l-yl]-5-nitro-pyrimidin-4-yl}-(2- fluoro-4-methanesulfonyl-phenyl)-amine B124

{6-[4-(3-tert-Butyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4- methanesulfony]-phenyl)-amine B125

[6-(4-Benzofuran-2-yl-piperidin- 1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine B126

4-(3-Fluoro-4-methanesulfonyl- phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin- 1-yl]-pyrimidine-5-carbonitrile B127

{6-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-{5- methanesulfonyl-pyridin-2-yl)- amineB128

(3-Fluoro-4-methanesulfonyl- phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl}-piperidin- 1-yl]-5-nitro-pyrimidin-4-yl}- amineB129

{6-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-l-yl]-5-nitro-pyrimidin-4-yl}-(6- methanesulfonyl-pyridin-3-yl)- amineB130

4-(2,3-Difluoro-phenylamino)-6- [4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine- 5-carbonitrile B131

4-(2,5-Difluoro-phenylamino)-6- [4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine- 5-carbonitrile B132

4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl- phenylamino)-pyrimidine-5- carbonitrile B133

4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-l-yl]-6-(4-methanesulfonyl- phenylamino)-pyrimidine-5- carbonitrile B134

4-(4-Hexanoyl-piperidin-1-yl)- 6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5- carbonitrile B135

4-(4-Hexanoyl-piperidin-1-yl)-6- (6-methanesulfonyl-pyridin-3-ylamino)-pyrimidine-5- carbonitrile B136

4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methylsulfanyl-pyridin- 3-ylamino)-pyrimidine-5- carbonitrileB137

4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl- pyridin-3-ylamino)-pyrimidine- 5-carbonitrileB138

1-[4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-6-{4-methanesulfonyl-phenylamino)- pyrimidin-5-yl]-ethanone B139

1-[4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl- pyridin-3-ylamino)-pyrimidin- 5-yl]-ethanone

TABLE C Cmpd# Structure Chemical Name C1 

1-(5-Nitro-6-phenyl-pyrimidin-4-yl)- piperidine-4-carboxylic acid ethylester C2 

1-(6-Naphthalen-2-yl-5-nitro- pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester C3 

1-[6-(4-Methanesulfonyl-phenyl)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C4 

1-(6-Benzofuran-5-yl-5-nitro- pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester C5 

1-[5-Nitro-6-(3-trinuoromethyl- phenyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C6 

1-[6-(4-Methoxy-phenyl)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester C7 

4-(4-Butyl-piperidin-1-yl)-6-furan-3-yl- 5-nitro-pyrimidine C8 

1-[6-(3-Chloro-phenyl)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester C9 

1-[6-(2,6-Dimethoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C10

1-(6-Naphthalen-1-yl-5-nitro- pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester C11

1-[6-(4-Methylsulfanyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C12

1-(2′,4′-Dihydroxy-5-nitro- [4,5′]bipyrimidinyl-6-yl)-piperidine-4-carboxylic acid ethyl ester C13

1-[6-(4-Methanesulfonyl-phenyl)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C14

1-[6-(3,5-Bis-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester C15

1-(6-Dibenzothiophen-4-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester C16

1-[6-(3,5-Dimethyl-isoxazol-4-yl)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C17

1-(5-Nitro-6-thiophen-2-yl-pyrimidin-4- yl)-piperidine-4-carboxylic acidethyl ester C18

1-[6-(3,5-Dichloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C19

1-(6-Dibenzofuran-4-yl-5-nitro- pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester C20

1-[6-(3,5-Dimethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C21

1-[6-(4-Acetyl-phenyl)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester C22

1-[6-(4-Ethanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C23

1-[6-(2-Fluoro-biphenyl-4-yl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C24

1-[6-(3-Methanesulfonyl-phenyl)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester C25

1-{6-[4-(2-Carboxy-ethyl)-phenyl]-5- nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester C26

1-{6-[4-(2-Methoxycarbonyl-ethyl)- phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid methyl ester C27

1-{6-[4-(2-Methoxycarbonyl-ethyl)- phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester

TABLE D Cmpd# Structure Chemical Name D1

1-[5-Nitro-6-(2-trifluoromethyl- phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester D2

1-(5-Nitro-6-phenylethynyl- pyrimidin-4-yl)-piperidine-4- carboxylicacid ethyl ester D3

1-[5-Nitro-6-(4-trifluoromethyl- phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester D4

1-(5-Nitro-6-m-tolylethynyl- pyrimidin-4-yl)-piperidine-4- carboxylicacid ethyl ester D5

1-[6-(2-Fluoro-phenylethynyl)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester D6

1-[5-Nitro-6-(3-trifluoromethyl- phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester

TABLE E Cmpd# Structure Chemical Name E1

5-Nitro-4-(5-phenyl- [1,3,4]oxadiazol-2-ylsulfanyl)-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1- yl]-pyrimidine

Some embodiments of the present invention include a pharmaceuticalcomposition comprising at least one compound according to any of thecompound embodiments disclosed herein and a pharmaceutically acceptablecarrier.

Additionally, compounds of Formula (Ia) encompass all pharmaceuticallyacceptable solvates, particularly hydrates, thereof. The presentinvention also encompasses diastereomers as well as optical isomers,e.g. mixtures of enantiomers including racemic mixtures, as well asindividual enantiomers and diastereomers, which arise as a consequenceof structural asymmetry in certain compounds of Formula (Ia). Separationof the individual isomers or selective synthesis of the individualisomers is accomplished by application of various methods which are wellknown to practitioners in the art.

Indications

In addition to the foregoing beneficial uses for compounds of thepresent invention disclosed herein, compounds of the invention areuseful in the prophylaxis or treatment of additional diseases. Withoutlimitation, these include the following.

The most significant pathologies in Type II diabetes are impairedinsulin signaling at its target tissues (“insulin resistance”) andfailure of the insulin-producing cells of the pancreas to secrete anappropriate degree of insulin in response to a hyperglycemic signal.Current therapies to treat the latter include inhibitors of the β-cellATP-sensitive potassium channel to trigger the release of endogenousinsulin stores, or administration of exogenous insulin. Neither of theseachieves accurate normalization of blood glucose levels and both carrythe risk of inducing hypoglycemia. For these reasons, there has beenintense interest in the development of pharmaceuticals that function ina glucose-dependent action, i.e. potentiators of glucose signaling.Physiological signaling systems which function in this manner arewell-characterized and include the gut peptides GLP1, GIP and PACAP.These hormones act via their cognate G-protein coupled receptor tostimulate the production of cAMP in pancreatic β-cells. The increasedcAMP does not appear to result in stimulation of insulin release duringthe fasting or preprandial state. However, a series of biochemicaltargets of cAMP signaling, including the ATP-sensitive potassiumchannel, voltage-sensitive potassium channels and the exocytoticmachinery, are modified in such a way that the insulin secretoryresponse to a postprandial glucose stimulus is markedly enhanced.Accordingly, agonists of novel, similarly functioning, β-cell GPCRs,including RUP3, would also stimulate the release of endogenous insulinand consequently promote normoglycemia in Type II diabetes.

It is also established that increased cAMP, for example as a result ofGLP1 stimulation, promotes β-cell proliferation, inhibits β-cell deathand thus improves islet mass. This positive effect on β-cell mass isexpected to be beneficial in both Type II diabetes, where insufficientinsulin is produced, and Type I diabetes, where β-cells are destroyed byan inappropriate autoimmune response.

It is also well-established that metabolic diseases exert a negativeinfluence on other physiological systems. Thus, there is often thecodevelopment of multiple disease states (e.g. type I diabetes, type IIdiabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia, obesity or cardiovascular disease in“Syndrome X”) or secondary diseases which clearly occur secondary todiabetes (e.g. kidney disease, peripheral neuropathy). Thus, it isexpected that effective treatment of the diabetic condition will in turnbe of benefit to such interconnected disease states.

Some embodiments of the present invention include a method forprophylaxis or treatment of a metabolic disorder or complicationsthereof in an individual comprising administering to the individual atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof. In some embodiments, themetabolic disorder or complications thereof is type I, type II diabetes,inadequate glucose tolerance, insulin resistance, hyperglycemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemiasyndrome X, or metabolic syndrome. In some embodiments, the metabolicdisorder is type II diabetes. In some embodiments, the metabolicdisorder is hyperglycemia. In some embodiments, the metabolic disorderis hyperlipidemia. In some embodiments, the metabolic disorder ishypertriglyceridemia. In some embodiments, the metabolic disorder istype I diabetes. In some embodiments, the metabolic disorder isdyslipidemia. In some embodiments, the metabolic disorder is syndrome X.In some embodiments, the individual is a mammal. In some embodiments,the mammal is a human.

Some embodiments of the present invention include a method ofcontrolling or decreasing weight gain of an individual comprisingadministering to the individual a therapeutically effective amount of acompound of the present invention or pharmaceutical composition thereof.In some embodiments, the individual is a mammal. In some embodiments,the mammal is a human. In some embodiments, the human has a body massindex of about 18.5 to about 45. In some embodiments, the human has abody mass index of about 25 to about 45. In some embodiments, the humanhas a body mass index of about 30 to about 45. In some embodiments, thehuman has a body mass index of about 35 to about 45.

One aspect of the present invention pertains to a compound of Formula(Ia), as described herein, for use in a method of treatment of the humanor animal body by therapy.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor comprising contacting the receptor with a compound ofthe present invention.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention. In some embodiments, the compoundis an agonist. In some embodiments, the compound is an inverse agonist.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor is prophylaxis or treatment of a metabolic disorder andcomplications thereof. In some embodiments, the metabolic disorder istype I, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia syndrome X, or metabolic syndrome. Insome embodiments, the metabolic disorder is type II diabetes. In someembodiments, the metabolic disorder is hyperglycemia. In someembodiments, the metabolic disorder is hyperlipidemia. In someembodiments, the metabolic disorder is hypertriglyceridemia. In someembodiments, the metabolic disorder is type I diabetes. In someembodiments, the metabolic disorder is dyslipidemia. In someembodiments, the metabolic disorder is syndrome X. In some embodiments,the individual is a mammal. In some embodiments, the mammal is a human.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor controls or reduces weight gain of the individual. In someembodiments, the individual is a mammal. In some embodiments, the mammalis a human. In some embodiments, the human has a body mass index ofabout 18.5 to about 45. In some embodiments, the human has a body massindex of about 25 to about 45. In some embodiments, the human has a bodymass index of about 30 to about 45. In some embodiments, the human has abody mass index of about 35 to about 45.

Some embodiments of the present invention include the use of a compoundof the present invention for production of a medicament for use inprophylaxis or treatment of a metabolic disorder. In some embodiments,the metabolic disorder is type II diabetes, inadequate glucosetolerance, insulin resistance, hyperglycemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, dyslipidemia syndrome X, ormetabolic syndrome.

Some embodiments of the present invention include the use of a compoundof the present invention for production of a medicament for use incontrolling or decreasing weight gain in an individual. In someembodiments, the individual is a mammal. In some embodiments, the mammalis a human. In some embodiments, the human has a body mass index ofabout 18.5 to about 45. In some embodiments, the human has a body massindex of about 25 to about 45. In some embodiments, the human has a bodymass index of about 30 to about 45. In some embodiments, the human has abody mass index of about 35 to about 45.

Compounds of the present invention are identified as an agonist or aninverse agonist using methods known to those skilled in art, such as anassay as described in Example 1. Accordingly, representative examples ofcompounds of the present invention that are agonists include thefollowing:

[6-(4-Benzenesulfonyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperazin-1-yl}-aceticacid ethyl ester;(2-Fluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;{6-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;{6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;{6-[4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine;{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-phenyl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;{6-[4-(3-Cyclopropylmethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyrimidin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-[6-(4-Carbamoylmethyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;4′-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;{6-[4-(2-Methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine;4′-(2-Amino-4-ethanesulfonyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carboxylicacid ethyl ester;4′-(4-Imidazol-1-yl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;(4-Methoxy-2-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone;4-{4-[6-(4-Cyclopropylmethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-{4-[5-Nitro-6-(4-propoxymethyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-{4-[6-(4-Butoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-{4-[6-(4-Isobutoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;{1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-(4-fluoro-phenyl)-methanone;(2,3-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2,4-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-{2-Nitro-3-[4-(3-oxo-butyl)-phenoxy]-phenyl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Acetyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;3′-Nitro-2′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylicacid ethyl ester;4-(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(4-{5-Nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(2,4-Difluoro-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine;4-(4-{6-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-cyclohexyl]-pyrimidine;4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-4-ylsulfanyl)-cyclohexyl]-pyrimidine;4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-(4-phenylsulfanyl-cyclohexyl)-pyrimidine;1-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Dimethylsulfamoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-ylamino}-phenyl)-phenyl-methanone;1-[6-(4-Cyclohexyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine;{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine;(2-Fluoro-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(3-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(Morpholine-4-sulfonyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;Benzo[1,3]dioxol-5-yl-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;(4-Fluoro-phenyl)-{1-[5-nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidin-4-yl}-methanone;[5-Nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine;(4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{6-[4-(4-methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;2-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine;{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(6-{4-[5-(4-Fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]piperidin-1-yl}-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-pyridin-2-ylmethyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;1-{6-[4-(2,5-Dioxo-imidazolidin-4-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-propionyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-[4-(3-Oxo-butyl)-phenoxy]-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Benzoyl-5-methoxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;3′-Nitro-4′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester; 1-[6-(4-Dimethylsulfamoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(4,5-Dichloro-imidazol-1-yl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;Benzo[1,3]dioxol-5-yl-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone;(2,5-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-{5-Nitro-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine-5-carbonitrile;5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine-5-carbaldehyde;5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carbaldehyde;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carboxylicacid;[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-yl]-methanol;[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-ylmethyl]-dimethyl-amine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfinyl-phenylamino)-pyrimidine-5-carbonitrile;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(4-trifluoromethoxy-phenoxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile;1-{1-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one;1-{1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one;{6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;{6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;[6-(4-Benzofuran-2-yl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amineand5-Nitro-4-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine.

Representative examples of compounds of the present invention that areinverse agonists include the following:

1-{6-[4-(2-Carboxy-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid methyl ester;1-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(2-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-(5-Nitro-6-phenylethynyl-pyrimidin-4-yl)-piperidine-4-carboxylic acidethyl ester;1-[5-Nitro-6-(4-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-(5-Nitro-6-m-tolylethynyl-pyrimidin-4-yl)-piperidine-4-carboxylic acidethyl ester;1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(Benzo[1,2,5]oxadiazol-5-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid methyl ester;2,6-Dimethyl-4-[6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-morpholine;1-{6-[4-(5-Hydroxy-pyrimidin-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-sulfo-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4′-Methoxy-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;4-(4,4-Difluoro-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine;1-{5-Nitro-6-[4-(4-oxo-cyclohexyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(2-Hydroxy-ethyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-3-carboxylicacid ethyl ester;1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethylamide;1-[6-(2-Methyl-5-phenyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-piperidin-1-yl-pyrimidine;1-[5-Acetylamino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Diacetylamino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid;1-{5-Nitro-6-[2-(2-trifluoromethyl-phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{5-Nitro-6-[2-(3-trifluoromethyl-phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[5-Di-(methanesulfonyl)amino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(3-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Methyl-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(2-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2,5-Dimethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(2-oxo-benzo[1,3]oxathiol-6-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(9H-Carbazol-2-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(9-oxo-9H-fluoren-2-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{5-Amino-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{5-Amino-6-[4-(hydroxy-phenyl-methyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(6-Chloro-pyridin-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(Benzo[1,3]dioxol-5-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Benzyloxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Bromo-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Chloro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Carbamoyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(2-Methoxy-ethyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Benzoyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(4-Hydroxy-benzenesulfonyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[5-Amino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester; Propionic acid1-[2-amino-5-formyl-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidin-4-ylester;4-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperazine-1-carboxylicacid ethyl ester;1-[6-(4′-Cyano-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;{4-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone;3-{4-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionicacid methyl ester;2-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-5-ethanesulfonyl-phenylamine;4-(4-Cyclopentyl-phenoxy)-6-(4,4-difluoro-piperidin-1-yl)-5-nitro-pyrimidine;1-[6-(2,6-Dichloro-4-methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(4-Chloro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(4-Hydroxy-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Cyanomethyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone;4-(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one;3-(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-3-oxo-propionicacid methyl ester;4-(4-Methyl-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine;4-(4-Bromo-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine;4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine;1-[5-Nitro-6-(2-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(3-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Bromo-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid amide;1-[5-Nitro-6-(2-oxo-2H-chromen-6-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3-Morpholin-4-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethoxy-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Benzoyl-phenoxy)-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone;{4-Methoxy-2-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone;4-{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2-one;5-Nitro-4-(4-propyl-piperidin-1-yl)-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine;3-{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionicacid methyl ester;5-Ethanesulfonyl-2-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenylamine;Benzo[1,3]dioxol-5-yl-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;1-[6-(4-Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3-Ethynyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Chloro-2-fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2,4-Difluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Bromo-2-fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;4-(3-Ethynyl-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine;4-(4-Chloro-2-fluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine;4-(2,4-Difluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine;1-[6-(3-Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;4-[4-(4-Methyl-benzyl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine;4-(3-Methanesulfonyl-pyrrolidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine;4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidine;4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine;1-[6-(4-Cyclopentyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-pyrrol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;4′-(4-Benzoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-trifluoromethyl-piperidin-1-yl)-pyrimidine;4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidine;4-(4-Bromo-2-fluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine;4-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-yloxy)-phenyl]-butan-2-one;2′-(4-Benzoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-4-carboxylicacid ethyl ester;(5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)-(3-trifluoromethyl-benzyl)-amine;1-[5-Nitro-6-(2-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;(5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)-(2-trifluoromethyl-benzyl)-amine;[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-yloxy)-phenyl]-phenyl-methanone;(4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone;1-{6-[4-(4-Fluoro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;(4-Fluoro-phenyl)-{4-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-methanone;4-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine;4-(4-Methoxymethyl-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine;4-{4-[6-(4-Methoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;1-{5-Nitro-6-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenylamino]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-(5-Nitro-6-phenyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethylester;1-(6-Naphthalen-2-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester;4-[4-(2-Methoxy-ethyl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine;4-{4-[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-yloxy)-phenyl]-butan-2-one;3′-Nitro-4-propyl-4′-(4-[1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl;1-[3-(4-Benzoyl-phenoxy)-2-nitro-phenyl]-piperidine-4-carboxylic acidethyl ester;{4-[6-(4-Ethoxy-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-(4-fluoro-phenyl)-methanone;1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-ol;2-{1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-ethanol;3-{1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-propionicacid;(1-{6-[4-(4-Fluoro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidin-4-yl)-(4-fluoro-phenyl)-methanone;1-[5-Nitro-6-(4-trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(3,4,5-trimethoxy-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;(5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)-(4-trifluoromethyl-benzyl)-amine;1-[5-Amino-6-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Amino-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Bromo-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(Methyl-phenyl-amino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[(6-Fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(2,2-Difluoro-benzo[1,3]dioxol-4-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2,2-Difluoro-benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(1,1-Dioxo-1H-1λ⁶-benzo[b]thiophen-6-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[(Furan-3-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[2-(4-Methoxy-phenoxy)-ethylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[2-(5-Methoxy-1H-indol-3-yl)-ethylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;(3-Fluoro-phenyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;(3-Methoxy-phenyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;1-{6-[(3-Fluoro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Benzoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3,5-Bis-trifluoromethyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3,5-Dimethoxy-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Heptyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;2′-(4-Benzoyl-phenylamino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-pentyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(3-Carboxy-propyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(3,4,5-trimethoxy-benzyl)-amine;(3,5-Dimethoxy-benzyl)-[₅-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;(4-{5-Nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]pyrimidin-4-ylamino}-phenyl)-phenyl-methanone;1-[6-(3,5-Difluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3,5-Dichloro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Bromo-4-trifluoromethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[(2-Fluoro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(Ethyl-phenyl-amino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[(4-Chloro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Difluoromethyl-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Cyano-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-sec-Butyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(Cyano-phenyl-methyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{5-Nitro-6-[4-(4-trifluoromethyl-phenoxy)-phenylamino]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Methyl-5-phenyl-2H-pyrazol-3-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Benzenesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(2-trifluoromethyl-3H-benzoimidazol-5-ylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-(6-Benzofuran-5-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;4-(4-Butyl-piperidin-1-yl)-6-furan-3-yl-5-nitro-pyrimidine;1-[6-(3-Chloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2,6-Dimethoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-(6-Naphthalen-1-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methylsulfanyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-(2′,4′-Dihydroxy-5-nitro-[4,5]bipyrimidinyl-6-yl)-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3,5-Bis-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-(6-Dibenzothiophen-4-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester;4-(2,4-Difluoro-phenoxy)-6-(4-ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidine;1-{4-[6-(4-Methoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-ethanone;4-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-butan-2-one;1-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-ethanone;{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-phenyl-methanone;3-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-3-oxo-propionicacid methyl ester;(4-Fluoro-phenyl)-[4-(3′-nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4′-yloxy)-phenyl]-methanone;1-[6-(3,5-Dimethyl-isoxazol-4-yl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-(5-Nitro-6-thiophen-2-yl-pyrimidin-4-yl)-piperidine-4-carboxylic acidethyl ester;1-[6-(3,5-Dichloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-(6-Dibenzofuran-4-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester;1-[6-(3,5-Dimethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Acetyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Ethanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Fluoro-biphenyl-4-yl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Fluoro-phenylethynyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester and1-[5-Nitro-6-(3-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester.

Pharmaceutical Compositions

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are available to those in the art; for example, seeRemington's Pharmaceutical Sciences, 16^(th) Edition, 1980, MackPublishing Co., (Oslo et al., eds.) and the most current version.

While it is possible that, for use in the prophylaxis or treatment, acompound of the invention may in an alternative use be administered as araw or pure chemical, it is preferable however to present the compoundor active ingredient as a pharmaceutical formulation or compositionfurther comprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers therefor and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not overly deleterious tothe recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

The dose when using the compounds of Formula (Ia) can vary within widelimits, and as is customary and is known to the physician, it is to betailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the Formula (Ia). Representative doses ofthe present invention include, about 0.01 mg to about 1000 mg, about0.01 to about 750 mg, about 0.01 to about 500 mg, 0.01 to about 250 mg,0.01 mg to about 200 mg, about 0.01 mg to 150 mg, about 0.01 mg to about100 mg, and about 0.01 mg to about 75 mg. Multiple doses may beadministered during the day, especially when relatively large amountsare deemed to be needed, for example 2, 3 or 4, doses. If appropriate,depending on individual behavior and as appropriate from the patientsphysician or care-giver it may be necessary to deviate upward ordownward from the daily dose.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. Typically, animal modelsinclude, but are not limited to, the rodents diabetes models asdescribed in Example 6, infra (other animal models have been reported byReed and Scribner in Diabetes, Obesity and Metabolism, 1, 1999, 75-86).In some circumstances, these extrapolations may merely be based on theweight of the animal model in comparison to another, such as a mammal,preferably a human, however, more often, these extrapolations are notsimply based on weights, but rather incorporate a variety of factors.Representative factors include the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized, onwhether an acute or chronic disease state is being treated orprophylaxis is conducted or on whether further active compounds areadministered in addition to the compounds of the Formula (Ia) and aspart of a drug combination. The dosage regimen for treating a diseasecondition with the compounds and/or compositions of this invention isselected in accordance with a variety factors as cited above. Thus, theactual dosage regimen employed may vary widely and therefore may deviatefrom a preferred dosage regimen and one skilled in the art willrecognize that dosage and dosage regimen outside these typical rangescan be tested and, where appropriate, may be used in the methods of thisinvention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavouringagents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of theFormula (Ia) or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the Formula (Ia) as an aerosol can be prepared by processeswell-known to the person skilled in the art. For their preparation, forexample, solutions or dispersions of the compounds of the Formula (Ia)in water, water/alcohol mixtures or suitable saline solutions can beemployed using customary additives, for example benzyl alcohol or othersuitable preservatives, absorption enhancers for increasing thebioavailability, solubilizers, dispersants and others, and, ifappropriate, customary propellants, for example include carbon dioxide,CFC's, such as, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference.

Combination Therapy/Prophylaxis

While the compounds of the invention can be administered as the soleactive pharmaceutical agent as described herein above, they can also beused in combination with one or more agents belonging to the class ofdrugs known as α-glucosidase inhibitors, aldose reductase inhibitors,biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors,fibrate compounds, LDL catabolism enhancers and angiotensin convertingenzyme (ACE) inhibitors.

α-Glucosidase inhibitors belong to the class of drugs whichcompetitively inhibit digestive enzymes such as α-amylase, maltase,α-dextrinase, sucrase, etc. in the pancreas and or small intestine. Thereversible inhibition by α-glucosidase inhibitors retard, diminish orotherwise reduce blood glucose levels by delaying the digestion ofstarch and sugars. Some representative examples of α-glucosidaseinhibitors include acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine(generic name; voglibose), miglitol, and α-glucosidase inhibitors knownin the art.

The class of aldose reductase inhibitors are drugs which inhibit thefirst-stage rate-limiting enzyme in the polyol pathway that prevent orarrest diabetic complications. In the hyperglycemic state of diabetes,the utilization of glucose in the polyol pathway is increased and theexcess sorbitol accumulated intracellularly as a consequence acts as atissue toxin and hence evokes the onset of complications such asdiabetic neuropathy, retinopathy, and nephropathy. Examples of thealdose reductase inhibitors include tolurestat; epalrestat;3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid;2,7-difluorospiro(9H-fluorene-9,4′-imidazolidine)-2′,5′-dione (genericname: imirestat);3-[(4-bromo-2-fluorophenyl)methy]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid (generic name: zenarestat);6-fluoro-2,3-dihydro-2′,5′-dioxo-spiro[4H-1-benzopyran-4,4′-imidazolidine]-2-carboxamide(SNK-860); zopolrestat; sorbinil; and1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209),and aldose reductase inhibitors known in the art.

The biguanides are a class of drugs that stimulate anaerobic glycolysis,increase the sensitivity to insulin in the peripheral tissues, inhibitglucose absorption from the intestine, suppress of hepaticgluconeogenesis, and inhibit fatty acid oxidation. Examples ofbiguanides include phenformin, metformin, buformin, and biguanides knownin the art.

Statin compounds belong to a class of drugs that lower blood cholesterollevels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA) reductase.HMG-CoA reductase is the rate-limiting enzyme in cholesterolbiosynthesis. A statin that inhibits this reductase lowers serum LDLconcentrations by upregulating the activity of LDL receptors andresponsible for clearing LDL from the blood. Examples of the statincompounds include rosuvastatin, pravastatin and its sodium salt,simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, andHMG-CoA reductase inhibitors known in the art.

Squalene synthesis inhibitors belong to a class of drugs that lowerblood cholesterol levels by inhibiting synthesis of squalene. Examplesof the squalene synthesis inhibitors include(S)-α-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, mono potassium salt (BMS-188494) and squalene synthesis inhibitorsknown in the art.

Fibrate compounds belong to a class of drugs that lower bloodcholesterol levels by inhibiting synthesis and secretion oftriglycerides in the liver and activating a lipoprotein lipase. Fibrateshave been known to activate peroxisome proliferators-activated receptorsand induce lipoprotein lipase expression. Examples of fibrate compoundsinclude bezafibrate, beclobrate, binifibrate, ciplofibrate,clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate,gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate,theofibrate, and fibrates known in the art.

LDL (low-density lipoprotein) catabolism enhancers belong to a class ofdrugs that lower blood cholesterol levels by increasing the number ofLDL (low-density lipoprotein) receptors, examples include LDL catabolismenhancers known in the art.

Angiotensin converting enzyme (ACE) inhibitors belong to the class ofdrugs that partially lower blood glucose levels as well as loweringblood pressure by inhibiting angiotensin converting enzymes. Examples ofthe angiotensin converting enzyme inhibitors include captopril,enalapril, alacepril, delapril; ramipril, lisinopril, imidapril,benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,moveltopril, perindopril, quinapril, spirapril, temocapril,trandolapril, and angiotensin converting enzyme inhibitors known in theart.

Insulin secretion enhancers belong to the class of drugs having theproperty to promote secretion of insulin from pancreatic β cells.Examples of the insulin secretion enhancers include sulfonylureas (SU).The sulfonylureas (SU) are drugs which promote secretion of insulin frompancreatic β cells by transmitting signals of insulin secretion via SUreceptors in the cell membranes. Examples of the sulfonylureas includetolbutamide; chlorpropamide; tolazamide; acetohexamide;4-chloro-N-[(1-pyrrolidinylamino)carbonyl]-benzenesulfonamide (genericname: glycopyramide) or its ammonium salt; glibenclamide (glyburide);gliclazide; 1-butyl-3-metanilylurea; carbutamide; glibonuride;glipizide; gliquidone; glisoxepid; glybuthiazole; glibuzole;glyhexamide; glymidine; glypinamide; phenbutamide; tolcyclamide,glimepiride, and other insulin secretion enhancers known in the art.Other insulin secretion enhancers includeN-[[4-(1-methylethyl)cyclohexyl)carbonyl]-D-phenylalanine (Nateglinide);calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionatedihydrate (Mitiglinide, KAD-1229); and other insulin secretion enhancersknown in the art.

Thiazolidinediones belong to the class of drugs more commonly known asTZDs. Examples of thiazolidinediones include rosiglitazone,pioglitazone, and thiazolidinediones known in the art.

Some embodiments of the invention include, a pharmaceutical compositioncomprising a compound of Formula (Ia) or a pharmaceutically acceptablesalt thereof in combination with at least one member selected from thegroup consisting of an α-glucosidase inhibitor, an aldose reductaseinhibitor, a biguanide, a HMG-CoA reductase inhibitor, a squalenesynthesis inhibitor, a fibrate compound, a LDL catabolism enhancer andan angiotensin converting enzyme inhibitor. In another embodiment, thepharmaceutical composition is a compound of Formula (Ia) or apharmaceutically acceptable salt thereof in combination with a HMG-CoAreductase inhibitor. In still another embodiment, the HMG-CoA reductaseinhibitor is selected from the group consisting of prevastatin,simvastatin, lovastatin, atorvastatin, fluvastatin and lipitor.

In accordance with the present invention, the combination can be used bymixing the respective active components either all together orindependently with a physiologically acceptable carrier, excipient,binder, diluent, etc., as described herein above, and administering themixture or mixtures either orally or non-orally as a pharmaceuticalcomposition. When a compound or a mixture of compounds of Formula (Ia)are administered as a combination therapy or prophylaxis with anotheractive compound the therapeutic agents can be formulated as a separatepharmaceutical compositions given at the same time or at differenttimes, or the therapeutic agents can be given as a single composition.

Other Utility

Another object of the present invention relates to radiolabelledcompounds of Formula (Ia) that would be useful not only in radio-imagingbut also in assays, both in vitro and in vivo, for localizing andquantitating RUP3 in tissue samples, including human, and foridentifying RUP3 ligands by inhibition binding of a radiolabelledcompound. It is a further object of this invention to develop novel RUP3assays of which comprise such radiolabelled compounds.

Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ³H (also written as T),¹¹C, ¹⁴C, ¹⁸F, ¹²⁵I, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ¹⁵O, ¹³N,³⁵S and ⁷⁷Br. The radionuclide that is incorporated in the instantradiolabelled compounds will depend on the specific application of thatradiolabelled compound. Thus, for in vitro RUP3 labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ¹²⁵I, ¹³¹I, ³⁵S or ⁸²Br willgenerally be most useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labelled” or “labelled compound” is acompound of Formula (Ia) that has incorporated at least oneradionuclide; In some embodiments, the radionuclide is selected from thegroup consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br; In some embodiments,the radionuclide ³H or ¹⁴C. Moreover, it should be understood that allof the atoms represented in the compounds of the invention can be eitherthe most commonly occurring isotope of such atoms or the more scarceradio-isotope or nonradio-active isotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds including those applicable to those compounds of the inventionare well known in the art and include incorporating activity levels oftritium into target molecules include: A. Catalytic Reduction withTritium Gas—This procedure normally yields high specific activityproducts and requires halogenated or unsaturated precursors. B.Reduction with Sodium Borohydride [³H]—This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters, and the like. C.Reduction with Lithium Aluminum Hydride [³H]—This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters, and the like. D. Tritium Gas ExposureLabeling—This procedure involves exposing precursors containingexchangeable protons to tritium gas in the presence of a suitablecatalyst. E. N-Methylation using Methyl Iodide [³H]—This procedure isusually employed to prepare O-methyl or N-methyl (³H) products bytreating appropriate precursors with high specific activity methyliodide (³H). This method in general allows for high specific activity,such as about 80-87 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include: A. Sandmeyer and like reactions—This proceduretransforms an aryl or heteroaryl amine into a diazonium salt, such as atetrafluoroborate salt, and subsequently to ¹²⁵I labelled compound usingNa¹²⁵I. A represented procedure was reported by Zhu, D.-G. andco-workers in J. Org. Chem. 2002, 67, 943-948. B. Ortho ¹²⁵Iodination ofphenols—This procedure allows for the incorporation of ¹²⁵I at the orthoposition of a phenol as reported by Collier, T. L. and co-workers in J.Labelled Compd Radiopharm. 1999, 42, S264-S266. C. Aryl and heteroarylbromide exchange with ¹²⁵I—This method is generally a two step process.The first step is the conversion of the aryl or heteroaryl bromide tothe corresponding tri-alkyltin intermediate using for example, a Pdcatalyzed reaction [i.e. Pd(Ph₃P)₄] or through an aryl or heteroaryllithium, in the presence of a tri-alkyltinhalide or hexaalkylditin[e.g., (CH₃)₃SnSn(CH₃)₃]. A represented procedure was reported by Bas,M.-D. and co-workers in J. Labelled Compd Radiopharm. 2001, 44,S280-S282.

A radiolabelled RUP3 compound as described herein can be used in ascreening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radiolabelledcompound of Formula (Ia)” to the RUP3 receptor. Accordingly, the abilityof a test compound to compete with the “radio-labelled compound ofFormula (Ia)” for the binding to the RUP3 receptor directly correlatesto its binding affinity.

The labelled compounds of the present invention bind to the RUP3receptor. In one embodiment the labelled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labelled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labelled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment thelabelled compound has an IC₅₀ less than about 1 μM, and in still yetanother embodiment the labelled inhibitor has an IC₅₀ less than about0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those in the art based upon, inter alia, a review of this patentdocument.

This application claims priority benefit of U.S. Provisional ApplicationNo. 60/440,394, filed Jan. 14, 2003; U.S. Provisional Patent ApplicationNo. 60/449,829, filed Feb. 24, 2003, U.S. Provisional Patent ApplicationNo. 60/453,390, filed Mar. 6, 2003, and U.S. Non-Provisional PatentApplication No. 60/470,875, filed May 14, 2003; wherein each are herebyincorporated by reference in their entirety.

The following examples are given to illustrate the invention and are notintended to be inclusive in any manner:

EXAMPLES

The compounds of the present invention and their syntheses are furtherillustrated by the following examples. The examples are provided tofurther define the invention without, however, limiting the invention tothe specifics of these examples.

Example 1 96-Well Cyclic AMP Membrane Assay for RUP3 Materials:

-   1) Adenlyl cyclase Activation Flashplate Assay kit from Perkin    Elmer—96 wells (SMP004B) and ¹²⁵I tracer (NEX130) which comes with    the kit. Keep in refrigerator, in a box, and do not expose the    Flashplates to light.-   2) Phosphocreatine—Sigma P-7936-   3) Creatine Phosphokinase—Sigma C-3755-   4) GTP—Sigma G-8877-   5) ATP—Sigma A-2383-   6) IBMX—Sigma I-7018-   7) Hepes—1M solution in distilled water—Gibco #15630080-   8) MgCl2—Sigma M-1028—1M Solution-   9) NaCl—Sigma—S6546—5M Solution-   10) Bradford Protein Assay Kit—Biorad #5000001-   11) Proclin 300—Sigma #4-8126

Binding Buffer—filter through 45-micron Nalgene filter and keep inrefrigerator. All buffers and membranes should be kept cold (in icebucket) while performing assay.

20 mM Hepes, pH7.4 1 mM MgCl2 100 mM NaCl

2× Regeneration Buffer (make in binding buffer):20 mM Phosphocreatine (1.02 gm/200 ml binding buffer)20 units Creatine phosphokinase (4 mg/200 ml)20 uM GTP (make up 10.46 mg/ml in binding buffer and add 200 ul/200 ml)0.2 mM ATP (22.04 mg/200 ml)100 mM IBMX (44.4 mg IBMX dissolved in 1 ml 100% DMSO first and then addthe entire amount to 200 ml of buffer).

Regeneration buffer can be aliquotted into 40-45 ml portions (in 50 mlsterile tubes) and kept frozen for up to 2 months. Simply put the tubein a beaker with room temperature water to thaw out the regenerationbuffer on the day of the assay.

A. Assay Procedure

-   -   1) Pipet 50 ul regeneration buffer in all 96 wells using Matrix        1250 8-channel pipettor.    -   2) Pipet 5 ul DMSO in columns 1 and columns 11 and 12.    -   3) Pipet 50 ul cAMP standards in columns 11 and 12 in this        format: 50 pmole/well for row A, 25 pmole/well for row B, 12.5        pmol/well for row C, 5 picomol/well for row D, 2.5 pmole/well        for row E, 1.25 pmole/well for row F, 0.5 pmole/well for row G,        and 0 pmole/well (buffer only) for row H.    -   4) Pipet 5 ul compounds from each well of a compound dilution        plate, for IC50s, using the following dilution scheme:        -   Well H: 400 uM compound (final concentration of compound in            reaction mix=5/100×400 uM=20 uM        -   Well G: 1:10 dilution of Well H (i.e. 5 ul compound from            well H+45 ul 100% DMSO) (final concentration=2 uM)        -   Well F: 1:10 dilution of well G (final concentration=0.2 uM)        -   Well E: 1:10 dilution of well F (final concentration=0.02            uM)        -   Well D: 1:10 dilution of well E (final concentration=0.002            uM)        -   Well C: 1:10 dilution of well D (final concentration=0.0002            uM        -   Well B: 1:10 dilution of well C (final concentration=0.00002            uM)        -   Well A: 1:10 dilution of well B (final            concentration=0.000002 uM)        -   IC₅₀s or EC₅₀s are done in triplicate. One Flashplate can            therefore be set up to handle 3 compounds. (i.e., columns 2,            3, and 4 are for compound #1, columns 5, 6, and 7 are for            compound #2, and columns 8, 9, and 10 are for compound #3.)    -   5) Add 50 ul of RUP3 membranes to all wells in Columns 2 to 10.        (Prior to the start of the assay, the frozen membrane pellets        for both RUP3 and CMV (cells transfected with an expression        plasmid containing no RUP3 sequences), are suspended in binding        buffer, usually 1 ml binding buffer for 1 plate of membranes.        The membranes are kept in ice all the time, and a polytron        (Brinkmann polytron, model PT-3100) is used (setting 6-7, for        15-20 seconds) to obtain a homogeneous membrane suspension.)        Protein concentration is determined by Bradford protein assay        kit using instructions given in the kit, using the standard        supplied with the kit as a reference. The protein concentration        of the membranes is adjusted with binding buffer, so that 50 ul        membranes=15 ug protein (i.e. 0.3 mg/ml protein).    -   6) In column 1, Wells A, B, C, and D, add 50 ul RUP3 membranes.        To wells E, F, G, and H, add 50 ul CMV membranes, (CMV membranes        being of the same protein concentration as the RUP3 membranes).    -   7) Incubate 1 hour at room temperature with agitation on a        rotating platform shaker. Cover with foil while shaking.    -   8) After 1 hour, add (to all 96 wells), 100 ul of the ¹²⁵I        tracer in detection buffer supplied with the Flashplate kit plus        proclin, made up in the following manner:

Pipet per 10 ml per Flashplate: 100 ml of detection buffer+1 ml ¹²⁵I+0.2ml of Proclin (the proclin helps to stop the production of cAMP). Make asmaller quantity of detection buffer mix if you have fewer plates.

-   -   9) Shake the plates on a rotating platform shaker for 2 hours,        covering the plates with lead sheeting.    -   10) Seal the plates with the plastic film sealers provided with        the Flashplate kit    -   11) Count the plates using a TRILUX 1450 Microbeta Counter. See        the door of the counter to determine which counting protocol to        use.    -   12) Data is analyzed on the Arena Database according to the RUP3        non-fusion, IC₅₀ EC₅₀ for 96-well cAMP membrane assay, and the        compound numbers and the concentrations of compounds must be        entered by the user.

B. Membrane Cyclase Criteria

-   -   1) Signal to Noise:        -   An acceptable signal-to-noise ratio for RUP3 can vary from 4            to 6. The raw cpms are approximately 1800 to 2500 for RUP3            and 3500-4500 for CMV. The cpm (or ultimately pmoles of            cAMP/well) cannot be outside the standard curve, and should            not approach well A of the standard curve (50 pmole/well)            and well H (no cAMP). Generally, the pmoles of cAMP produced            by RUP3 receptor are around 11 to 13 pmole/well (for 15            ug/well protein), and for CMV are between 2 to 3 pmole/well            (for 15 ug protein/well).    -   2) Standard curve:        -   The slope should be linear and the error bars for duplicates            should be very small. The receptor and CMV controls cannot            be off scale of the standard curve, as described above. If            the receptor controls are off the high end of the standard            curve, i.e. 50 pmole/well or higher, one must repeat the            experiment using less protein. However, such a case has not            been observed with transiently transfected RUP3 membranes            (10 ug DNA/15 cm plate, using 60 ul Lipofectamine, and            preparing membranes after 24 hour of transfection.)    -   3) The IC₅₀ or EC₅₀ curve should be at 100% (+ or −20%) of        control RUP3 membranes at the top, and should go down to 0 (or        up to 20%) at the bottom. The standard error of the triplicate        determinations should be + or −10%.        C. Stimulation of cAMP in HIT-T15 Cells

HIT-T15 (ATCC CRL#1777) is an immortalized hamster insulin-producingcell line. These cells express RUP3 and therefore can be used to assessthe ability of RUP3 ligands to stimulate or inhibit cAMP accumulationvia its endogenously expressed receptor. In this assay, cells are grownto 80% confluence and then distributed into a 96-well Flashplate (50,000cells/well) for detection of cAMP via a “cAMP Flashplate Assay” (NEN,Cat # SMP004). Briefly, cells are placed into anti-cAMP antibody-coatedwells that contain either vehicle, the test ligand(s) at a concentrationof interest, or 1 uM forskolin. The latter is a direct activator ofadenylyl cyclase and serves as a positive control for stimulation ofcAMP in HIT-T15 cells. All conditions are tested in triplicate. After a1 hour incubation to allow for stimulation of cAMP, a Detection Mixcontaining ¹²⁵I-cAMP is added to each well and the plate is allowed toincubate for another 1 hour. The wells are then aspirated to removeunbound ¹²⁵I-cAMP. Bound ¹²⁵I-cAMP is detected using a Wallac MicrobetaCounter. The amount of cAMP in each sample is determined by comparisonto a standard curve, obtained by placing known concentrations of cAMP insome wells on the plate.

D. Stimulation of Insulin Secretion in HIT-T15 Cells

It is known that stimulation of cAMP in HIT-T15 cells causes an increasein insulin secretion when the glucose concentration in the culture mediais changed from 3 mM to 15 mM. Thus, RUP3 ligands can also be tested fortheir ability to stimulate glucose-dependent insulin secretion (GSIS) inHIT-T15 cells. In this assay, 30,000 cells/well in a 12-well plate areincubated in culture media containing 3 mM glucose and no serum for 2hours. The media is then changed; wells receive media containing either3 mM or 15 mM glucose, and in both cases the media contains eithervehicle (DMSO) or RUP3 ligand at a concentration of interest. Some wellsreceive media containing 1 uM forskolin as a positive control. Allconditions are tested in triplicate. Cells are incubated for 30 minutes,and the amount of insulin secreted into the media is determined byELISA, using a kit from either Peninsula Laboratories (Cat # ELIS-7536)or Crystal Chem Inc. (Cat # 90060).

E. Stimulation of Insulin Secretion in Isolated Rat Islets

As with HIT-T15 cells, it is known that stimulation of cAMP in isolatedrat islets causes an increase in insulin secretion when the glucoseconcentration in the culture media is changed from 60 mg/dl to 300mg/dl. RUP3 is an endogenously expressed GPCR in the insulin-producingcells of rat islets. Thus, RUP3 ligands can also be tested for theirability to stimulate GSIS in rat islet cultures. This assay is performedas follows:

-   -   A. Select 75-150 islet equivalents (IEQ) for each assay        condition using a dissecting microscope. Incubate overnight in        low-glucose culture medium. (Optional.)    -   B. Divide the islets evenly into triplicate samples of 25-40        islet equivalents per sample. Transfer to 40 μm mesh sterile        cell strainers in wells of a 6-well plate with 5 ml of low (60        mg/dl) glucose Krebs-Ringers Buffer (KRB) assay medium.    -   C. Incubate 30 minutes (1 hour if overnight step skipped) at        37° C. and 5% CO₂. Save the supernatants if a positive control        for the RIA is desired.    -   D. Move strainers with islets to new wells with 5 ml/well low        glucose KRB. This is the second pre-incubation and serves to        remove residual or carryover insulin from the culture medium.        Incubate 30 minutes.    -   E. Move strainers to next wells (Low 1) with 4 or 5 ml low        glucose KRB. Incubate @ 37° C. for 30 minutes. Collect        supernatants into low-binding polypropylene tubes pre-labelled        for identification and keep cold.    -   F. Move strainers to high glucose wells (300 mg/dl, which is        equivalent to 16.7 mM). Incubate and collect supernatants as        before. Rinse islets in their strainers in low-glucose to remove        residual insulin. If the rinse if to be collected for analysis,        use one rinse well for each condition (i.e. set of triplicates.)    -   G. Move strainers to final wells with low-glucose assay medium        (Low 2). Incubate and collect supernatants as before.    -   H. Keeping cold, centrifuge supernatants at 1800 rpm for 5        minutes @ 4-8° C. to remove small islets/islet pieces that        escape the 40 mm mesh. Remove all but lower 0.5-1 ml and        distribute in duplicate to pre-labelled low-binding tubes.        Freeze and store at <−20° C. until insulin concentrations can be        determined.    -   I. Insulin determinations are done as above, or by Linco Labs as        a custom service, using their rat insulin RIA (Cat. # RI-13K).

Example 2 A. RT-PCR Analysis of RUP3 Expression in Human Tissues (FIG.1A).

RT-PCR was applied to determine the tissue distribution of RUP3.Oligonucleotides used for PCR had the following sequences:

ZC47: (SEQ ID NO: 3) 5′-CATTGCCGGGCTGTGGTTAGTGTC-3′ (forward primer),;ZC48: (SEQ ID NO: 4) 5′-GGCATAGATGAGTGGGTTGAGCAG-3′ (reverse primer),;

and the human multiple tissue cDNA panels (MTC, Clontech) were used astemplates (1 ng cDNA per PCR amplification). Twenty-two (22) humantissues were analyzed. PCR was performed using Platinum PCR SuperMix(Life Technologies, Inc.; manufacture instructions were followed) in a50 μl reaction by the following sequences: step 1, 95° C. for 4 min;step 2, 95° C. for 1 min; step 3, 60° C. for 30 sec; step 4, 72° C. for1 min; and step 5, 72° C. for 7 min. Steps 2 through 4 were repeated 35times.

The resulting PCR reactions (15 μl) were loaded on a 1.5% agarose gel toanalyze the RT-PCR products, and a specific 466 base-pair DNA fragmentrepresenting RUP3 was specifically amplified from cDNA of pancreasorigin. Low expression was also evident in subregions of brain.

B. cDNA Dot-Blot Analysis of RUP3 Expression in Human Tissues (FIG. 1B).

Results from RT-PCR analysis were further confirmed in cDNA dot-blotanalysis. In this assay, a dot-blot membrane containing cDNA from 50human tissues (Clontech) was hybridized with a ³²P-radiolabelled DNAprobe having sequences derived from human RUP3. Hybridization signalswere seen in pancreas and fetal liver, suggesting these tissues expressRUP3. No significant expression was detected in other tissues analyzed.

C. Analysis of RUP3 by RT-PCR with Isolated Human Pancreatic Islets ofLangerhans (FIG. 1C)

Further analysis of RUP3 by RT-PCR with isolated human pancreatic isletsof Langerhans showed robust expression of RUP3 in islet cells but not incontrol samples.

D. Analysis of RUP3 Expression with cDNAs of Rat Origin by RT-PCR (FIG.1D)

RUP3 expression was further analyzed with cDNAs of rat origin by RT-PCRtechnique. Tissue cDNAs used for this assay were obtained from Clontechexcept those for hypothalamus and islets, which were prepared in house.Concentrations of each cDNA sample were normalized via a control RT-PCRanalysis of the house-keeping gene GAPDH before assaying for RUP3expression. Oligonucleotides used for PCR had the following sequences:

rat RUP3 (“rRUP3”) forward: 5′-CATGGGCCCTGCACCTTCTTTG-3′; (SEQ ID NO: 5)rRUP3 reverse: 5′-GCTCCGGATGGCTGATGATAGTGA-3′. (SEQ ID NO: 6)PCR was performed using Platinum PCR SuperMix (Life Technologies, Inc.;manufacture instructions were followed) in a 50 μl reaction by thefollowing sequences: step 1, 95° C. for 4 min; step 2, 95° C. for 1 min;step 3, 60° C. for 30 sec; step 4, 72° C. for 1 min; and step 5, 72° C.for 7 min. Steps 2 through 4 were repeated 35 times.

The resulting PCR reactions (15 μl) were loaded on a 1.5% agarose gel toanalyze the RT-PCR products, and a specific 547 base-pair DNA fragmentrepresenting rat RUP3 was specifically amplified from cDNA of pancreasorigin, revealing a similar expression profile with human. Of particularnote, robust expression was seen in isolated islets and hypothalamus.

Example 3 RUP3 Protein Expression is Restricted to β Cell Lineage ofPancreatic Islets (FIG. 2)

A. A Polyclonal Anti-RUP3 Antibody was Prepared in Rabbits (FIG. 2A).

Rabbits were immunized with an antigenic peptide with sequence derivedfrom rat RUP3 (“rRUP3”). The peptide sequence wasRGPERTRESAYHIVTISHPELDG and shared 100% identity with mouse RUP3 in thecorresponding region. A cysteine residue was incorporated at theN-terminal end of this antigenic peptide to facilitate KLH crosslinkingbefore injecting into rabbits. The resulting antisera (“anti-rRUP3”) andthe corresponding preimmune sera (“pre-rRUP3”) were tested for immunereactivity to mouse RUP3 in immunobloting assays (lanes 1 thought 4). Inthis assay, the GST-RUP3 fusion protein was readily recognized by theanti-rRUP3 antisera (lane 4), but not by the preimmune sera (lane 2).The immunoreactive signal could be efficiently eliminated when theimmunobloting assay was performed in the presence of excess antigenicpeptide (lane 6).

B. RUP3 Expression in Insulin-Producing β Cells of Pancreatic Islets(FIG. 2B).

Rat pancreas was perfused with 4% paraformaldehyde (PFA) in PBS andembedded in OCT embedding medium. Ten micron sections were prepared,fixed on glass slides, and immunostained with either pre-rRUP3 (FIG. 2B,panel a) or with anti-rRUP3 antisera (FIG. 2B, panels c and e) followedby secondary staining with donkey anti-rabbit IgG conjugated to thefluorochrome Cy-3. Each section was also co-immunostained with amonoclonal anti-insulin antibody (Santa Cruz, FIG. 2B, panels b and d)in primary staining followed by a secondary staining with donkeyanti-mouse IgG conjugated with FITC, or with a goat anti-glucagonantibody (Santa Cruz, FIG. 2B, panel f) and donkey anti-goat IgG coupledto FITC. Immunofluorescent signals were examined under a fluorescentmicroscope. RUP3 was found expressed in insulin producing cells (panelsc and d), but not in glucagons producing cells (panels e and f). Thesedata demonstrated that RUP3 is expressed in β cells but not in α cellsof the rat pancreatic islets. Analogous results were obtained when mousepancreatic sections were investigated for RUP3 expression.

Example 4 Functional Activities of RUP3 In Vitro (FIG. 3)

It was established that RUP3 stimulates the production of cAMP bycotransfection of 293 cells with: (1) a CRE-Luciferase reporter, whereinthe ability to stimulate the production of firefly luciferase depends onincreased cAMP in cells, and (2) an expression plasmid encoding thehuman form of RUP3 (FIG. 3A). Note that cells co-transfected with anexpression plasmid containing no RUP3 sequences (“CMV” in FIG. 3A)produce very little luciferase activity, whereas cells transfected withan expression plasmid encoding RUP3 (“RUP3” in FIG. 3A) have at least a10-fold increase in luciferase activity. This indicates that RUP3stimulates the production of cAMP when introduced into 293 cells. Thisproperty of RUP3 is conserved across species, because hamster RUP3stimulates luciferase activity when introduced into 293 cells in amanner analogous to that described for human RUP3 (FIG. 3B).

It is established that, when cAMP is increased in insulin-producingcells of the pancreas, these cells exhibit an enhanced ability tosecrete insulin when glucose concentrations rise. To test whether RUP3might impart enhanced glucose-dependent insulin release, retroviruscontaining human RUP3 was used to generate Tu6 cells that express highlevels of RUP3. Tu6 cells produce insulin, but do not expressappreciable levels of RUP3 and do not normally exhibit an increase ininsulin release when increased glucose is present in the culture media.As shown in FIG. 3C, Tu6 cells transduced with a control virus thatcontains no receptor are still able to produce insulin, but do not showan increase in insulin secretion when the concentration of glucose inthe culture media is shifted from 1 mM to 16 mM. By contrast, Tu6 cellstransduced with RUP3-containing retrovirus display significantglucose-dependent insulin secretion (FIG. 3C).

Example 5 Functional Activities of RUP3 Agonists In Vitro (FIG. 4)

To demonstrate that RUP3 agonists stimulate endogenously expressed RUP3in insulin-producing cells, two in vitro models can be used. In thefirst of these, RUP3 agonists are used to stimulate HIT-T15 cells, whichexpress RUP3 at significant levels, as indicated in the Northern blotshown in FIG. 4A. Moreover, these cells are known to exhibit enhancedglucose-dependent insulin release when intracellular cAMP concentrationsare elevated. In the example shown in FIG. 4B, the RUP3 agonist CompoundB84 stimulates cAMP production in HIT cells, at a level comparable tothat seen with the adenyl cyclase activator forskolin. This indicatesthat Compound B84 is a very robust stimulator of cAMP in HIT-T15 cells.In the example shown in FIG. 4C, Compound B84 also stimulates insulinsecretion in HIT cells exposed to 15 mM glucose, once again at a levelcomparable to that seen with the adenyl cyclase activator forskolin.This indicates that Compound B84 is a very robust potentiator of insulinsecretion in HIT-T15 cells.

Isolated rat islets are the other in vitro model used to demonstrate theefficacy of RUP3 agonists. In this model, agents that induce cAMP arenot expected to stimulate insulin secretion when glucose concentrationsare low (e.g. 60 mg/dl). However, when glucose concentrations areincreased (e.g. to 300 mg/dl), these agents are expected to enhanceinsulin secretion to levels above those seen with glucose alone. In theexample shown in FIG. 4D, both RUP3 agonists (Compounds 48 and 51 at 10uM concentration) enhanced glucose-dependent insulin release. Moreover,the level of enhancement was comparable to that seen with 25 nM GLP-1, agut hormone known to act on islets in this manner.

Example 6 In Vivo Effects of RUP3 Agonists on Glucose Homeostasis inMice

A. Oral Glucose Tolerance Test (oGTT) (FIG. 5A).

Male C57bl/6N mice at age of 8 weeks were fasted for 18 hours andrandomly grouped (n=11) to receive a RUP3 agonist (Compound B70) atindicated doses, or with control extendin-4 (ex-4, 1 μg/kg), a GLP-1peptide analog known to stimulate glucose-dependent insulin secretion.Compound B70 was delivered orally via a gavage needle (p.o. volume at100 μl). Control Ex-4 was delivered intraperitoneally. Thirty minutesafter administration of test compound and control ex-4, mice wereadministered orally with dextrose at 5 g/kg dose. Levels of bloodglucose were determined at the indicated time points using GlucometerElite XL (Bayer). FIG. 5A shows the mean glucose concentration averagedfrom eleven animals in each treatment group. These results demonstratedthat the RUP3 agonist, Compound B70, lowered blood glucose in adose-dependent manner in mice after challenged with glucose.

B. Acute Response of db Mice to RUP3 Agonist (FIG. 5B).

Male db mice (C57BL/KsOlahsd-Leprdb, diabetic, Harlan) at age of 10weeks were randomly grouped (n=6) to receive vehicle (oral gavage),Compound B70 (60 mg/kg, oral gavage), or Ex-4 (1 μg/kg,intraperitoneally). After compound administration, food was removed andblood glucose levels were determined at indicated times as shown in FIG.5B. Reduction in blood glucose at each time point was expressed aspercentage of original glucose levels, averaged from six animals foreach group. These animals had blood glucose levels (fed state) of300-400 mg/dl, significantly higher than non-diabetic wild type animals.Treatment with Compound B70 or Ex-4 significantly reduced glucose levelscompared to vehicle control as shown in FIG. 5B. These data demonstratedthat the RUP3 agonist had efficacy in improving glucose homeostasis indiabetic animals.

Example 7 CRE-Luciferase Assay in 293 Cells

293 cells were plated in 96-well tissue culture plates at aconcentration of 20,000 cells per well. The following day, the cells aretransfected with a mixture of pCRE-Luc (Stratagene, Cat. #219076), theindicated expression plasmid, and pEGFP-N1 (Clontech, Cat. #6085-1) at aratio of 5:1:0.25 using Lipofectamine Reagent (Invitrogen, Cat.#18324-020) according to the manufacturer's directions. pEGFP-N1 encodesa “green fluorescent protein” and was used as a control to determinethat most cells were successfully transfected. After 24-48 hr, the cellswere lysed in situ with 100 ul/well reconstituted Luclite buffer(Luclite Reporter Gene Assay Kit, Packard, Cat. #6016911), according tothe manufacturer's directions. After a 10 minute incubation in the dark,luminescence was measured using a TRILUX 1450 Microbeta Counter(Wallac).

Example 8 Generation of Tu6/RUP3 Stable Lines

To produce Tu6 cells that express RUP3 at high levels, a retrovirusbearing an expression cassette for RUP3 was generated. Briefly, RUP3coding sequence was cloned into the retroviral vector pLNCX2 (Clontech,Cat # 6102-1). The amphotropic packaging cell line PT-67 (Clontech,K1060-D) was then transfected with either the parental vector pLNCX2 orpLNCX2/RUP3 using Lipofectamine and stable lines were established usingguidelines provided by the PT-67 vendor. Retrovirus-containingsupernatant was obtained by collecting media from the resultant stablesaccording to the manufacturer's directions. Tu6 cells, in a 10 cm dish,were then infected with retrovirus by incubating in a solution of 1 mlviral supernatant/9 ml culture media containing 40 ug/ml polybrene for24 hours. The medium was then changed to culture media containing 300ug/ml G418. G418-resistant clones were ultimately created by virtue ofthe neomycin-resistance gene cassette present in the pLNCX2 vector, thusindicating the successful integration of retrovirus into the Tu6 genome.The expression of RUP3 in the Tu6/RUP3 G418-resistant colonies wasconfirmed by Northern blot.

Example 9 Insulin Secretion, Tu6 Stables

To measure insulin secretion from rodent insulin-producing cell lines,cells were first cultured overnight in serum-free, glucose-deficientmedia. The following morning, the cells were then placed in the samemedia supplemented with either 1 mM or 16 mM glucose. After anincubation of 4 hours, the media was collected and analyzed for insulincontent using a Rat Insulin Enzyme-Immunoassay (EIA) System (AmershamPharmacia Biotech, Cat # RPN 2567). Typically, the assay was performedusing multiple dilutions of sample media in order to ensure that thesample measurements fell within the boundaries of the standard curve(generated using known amounts of insulin), as recommended by themanufacturer.

Example 10 RUP3 RNA Blot

To determine the expression of RUP3 in insulin-producing or non isletcells, the following cell lines were obtained and cultured according toguidelines provided by American Type Culture Collection or the indicatedprovider.

Cell Line Provider Cat. # HIT-T15 American Type Culture CollectionCRL-1777 NIT-1 American Type Culture Collection CRL-2055 RIN-5F AmericanType Culture Collection CRL-2058 Tu-6 Ole Madsen, Hagedorn Res. Lab. N/AαTC-9 American Type Culture Collection CRL-2350 RIN-14B American TypeCulture Collection CRL-2059 ARIP American Type Culture CollectionCRL-1674 AR42J American Type Culture Collection CRL-1492 Panc-1 AmericanType Culture Collection CRL-1469 BxPc-3 American Type Culture CollectionCRL-1687 293 Q-Biogene AES0503 NIH-3T3 American Type Culture CollectionCRL-1658Total RNA was isolated from each of these cell lines using TRIZOL(Invitrogen, Cat #15596-018), subjected to electrophoresis through anagarose/formaldehyde gel and an RNA blot was prepared using standardmolecular biological techniques. A radiolabelled RUP3 probe,corresponding to the full-length coding sequence of RUP3, was preparedusing a Prime-It II Random Primer Labeling Kit (Stratagene, Cat#300385). The denatured probe, 10 ml ExpressHyb solution (Clontech, Cat# 8015-2) and the RNA blot were incubated in a hybridization oven,washed and exposed to film using standard molecular biology practices.

Example 11 Receptor Binding Assay

In addition to the methods described herein, another means forevaluating a test compound is by determining binding affinities to theRUP3 receptor. This type of assay generally requires a radiolabelledligand to the RUP3 receptor. Absent the use of known ligands for theRUP3 receptor and radiolabels thereof, compounds of Formula (Ia) can belabelled with a radioisotope and used in an assay for evaluating theaffinity of a test compound to the RUP3 receptor.

A radiolabelled RUP3 compound as described herein can be used in ascreening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radiolabelledcompound of Formula (Ia)” to the RUP3 receptor. Accordingly, the abilityto compete with the “radio-labelled compound of Formula (Ia)” orRadiolabelled RUP3 Ligand for the binding to the RUP3 receptor directlycorrelates to its binding affinity of the test compound to the RUP3receptor.

Assay Protocol for Determining Receptor Binding for RUP3:

A. RUP3 Receptor Preparation

293 cells (human kidney, ATCC), transiently transfected with 10 ug humanRUP3 receptor and 60 ul Lipofectamine (per 15-cm dish), were grown inthe dish for 24 hours (75% confluency) with a media change and removedwith 10 ml/dish of Hepes-EDTA buffer 20 mM Hepes+10 mM EDTA, pH 7.4).The cells were then centrifuged in a Beckman Coulter centrifuge for 20minutes, 17,000 rpm (JA-25.50 rotor). Subsequently, the pellet wasresuspended in 20 mM Hepes+1 mM EDTA, pH 7.4 and homogenized with a50-ml Dounce homogenizer and again centrifuged. After removing thesupernatant, the pellets were stored at −80° C., until used in bindingassay. When used in the assay, membranes were thawed on ice for 20minutes and then 10 mL of incubation buffer (20 mM Hepes, 1 mM MgCl₂,100 mM NaCl, pH 7.4) added. The membranes were then vortexed toresuspend the crude membrane pellet and homogenized with a BrinkmannPT-3100 Polytron homogenizer for 15 seconds at setting 6. Theconcentration of membrane protein was determined using the BRL Bradfordprotein assay.

B. Binding Assay

For total binding, a total volume of 50 ul of appropriately dilutedmembranes (diluted in assay buffer containing 50 mM Tris HCl (pH 7.4),10 mM MgCl₂, and 1 mM EDTA; 5-50 ug protein) is added to 96-wellpolyproylene microtiter plates followed by addition of 100 ul of assaybuffer and 50 ul of Radiolabelled RUP3 Ligand. For nonspecific binding,50 ul of assay buffer is added instead of 100 ul and an additional 50 ulof 10 uM cold RUP3 is added before 50 ul of Radiolabelled RUP3 Ligand isadded. Plates are then incubated at room temperature for 60-120 minutes.The binding reaction is terminated by filtering assay plates through aMicroplate Devices GF/C Unifilter filtration plate with a Brandell96-well plate harvestor followed by washing with cold 50 mM Tris HCl, pH7.4 containing 0.9% NaCl. Then, the bottom of the filtration plate aresealed, 50 ul of Optiphase Supermix is added to each well, the top ofthe plates are sealed, and plates are counted in a Trilux MicroBetascintillation counter. For compound competition studies, instead ofadding 100 ul of assay buffer, 100 ul of appropriately diluted testcompound is added to appropriate wells followed by addition of 50 ul ofRadiolabelled RUP3 Ligand.

C. Calculations

The test compounds are initially assayed at 1 and 0.1 μM and then at arange of concentrations chosen such that the middle dose would causeabout 50% inhibition of a Radio-RUP3 Ligand binding (i.e., IC₅₀).Specific binding in the absence of test compound (B_(O)) is thedifference of total binding (B_(T)) minus non-specific binding (NSB) andsimilarly specific binding (in the presence of test compound) (B) is thedifference of displacement binding (B_(D)) minus non-specific binding(NSB). IC₅₀ is determined from an inhibition response curve, logit-logplot of % B/B_(O) vs concentration of test compound.

K_(i) is calculated by the Cheng and Prustoff transformation:

K_(i)=IC₅₀/(1+[L]/K_(D))

where [L] is the concentration of a Radio-RUP3 Ligand used in the assayand K_(D) is the dissociation constant of a Radio-RUP3 Ligand determinedindependently under the same binding conditions.

Chemistry Syntheses of Compounds of the Present Invention Example 12

Illustrated syntheses for compounds of Formula (Ia) are shown in FIG. 6where the symbols have the same definitions as used throughout thisdisclosure. The preparation of N-oxides is well know in the art, whichinclude, but not limited to pyridines, pyrimidines and the like. Forexample, N-oxides can be prepared at normal or elevated pressure, in thepresence of an oxidizing agent, such as, hydrogen peroxide, peraceticacid, perbenzoic, m-chloroperbenzoic acid (mCPBA), ozone, oxygen and thelike, in the presence or absence of solvent, such as chloroform,dichlormethane, acetic acid, trifluoroacetic acid, and the like ormixtures thereof.

Chemistry: Proton nuclear magnetic resonance (¹H NMR) spectra wererecorded on a Varian Mercury Vx-400 equipped with a 4 nucleus autoswitchable probe and z-gradient or a Bruker Avance-400 equipped with aQNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient.Chemical shifts are given in parts per million (ppm) with the residualsolvent signal used as reference. NMR abbreviations are used as follows:s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad.Microwave irradiations were carried out using the Smith Synthesizer(Personal Chemistry). Thin-layer chromatography (TLC) was performed onsilica gel 60 F₂₅₄ (Merck), preparatory thin-layer chromatography (prepTLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman), andcolumn chromatography was carried out on a silica gel column usingKieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done in vacuo on aBuchi rotary evaporator. Celite 545® was used during palladiumfiltrations.

LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc;

HPLC system controller: SCL-10A VP, Shimadzu Inc.

UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: 215 Liquid Handler,Gilson Inc;

Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex

Software: Masschrom 1.52.

Compound A11-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester: General Method 1

A mixture of 1-(6-chloro-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester (63 mg, 0.2 mmol), 4-imidazol-1-yl-phenol (42 mg, 0.26mmol) and potassium carbonate (36 mg, 0.26 mmol, 1 equivalent) inanhydrous DMF (1 ml) was heated to 90° C. overnight. The resultingresidue was purified by Flash Chromatography (hexanes:ethyl acetate=1:1)to give1-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester [A1] as a yellow solid (80 mg, 92%). ¹H NMR (CDCl₃, 400MHz) δ 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m,1H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.38-7.42 (m, 2H),7.46 (t, 1H), 7.55-7.59 (m, 3H), 8.17 (s, 1H), 8.90-8.92 (m, 1H). Exactmass calculated for C₂₁H₂₂N₆O₃ 438.17, found 439.2 (MH⁺).

The intermediate1-(6-chloro-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethylester was prepared by following general method 2.

General Method 2: Addition of Substituted Piperidines todichloro-5-nitropyrimidine.

Compound 2,6-dichloro-5-nitropyrimidine (500 mg, 2.57 mmol) wasdissolved in dichloromethane (40 ml) and cooled to 0° C. To this wasadded diisopropylethyl amine (0.54 ml, 3.08 mmol) followed by a solutionof piperidine-4-ethyl-ester (3.69 mmol) in dichloromethane (5 ml)dropwise. The mixture was stirred at 0° C. for 1 hour and thenconcentrated in vacuo. Flash chromatography (hexanes:ethyl acetate=1:1)provided Compound A1a,1-(6-chloro-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethylester as a yellow solid (466 mg, 60%). ¹HNMR (DMSO, 400 MHz) δ 1.57-1.63(m, 2H), 1.91-1.95 (m, 2H), 2.72-2.74 (m, 1H), 3.17 (t, 2H), 3.60 (s,3H), 3.84-3.89 (m, 2H), 8.46 (s, 1H). Exact mass calculated forC₁₁H₁₃ClN₄O₄ 300.06, found 301.2 (MH⁺).

Compounds A2-A155 were prepared in an analogous manner as described forCompound A1, supra.

Compound A21-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester. General Method 3

4,6-dichloro-5-nitro pyrimidine (5.00 g, 25.7 mmol) anddiisopropylethylamine (7.66 ml, 43.9 mmol) were dissolved indichloromethane (17.0 ml). The mixture was stirred in an ice bath and4-ethyl ester piperidine (3.33 ml, 43.9 mmol) dissolved indichloromethane (17.0 ml) was added dropwise. The mixture was warmed toroom temperature and after 30 min. the desired product was observed byLCMS m/z 315 (M+H⁺). The solvent was removed under reduced pressure, thecrude dissolved in dioxane (20 ml), sequentially, diisopropylethylamine(6.31 ml, 36.22 mmol) and2-Methyl-5-trifluoromethyl-2H-3-hydroxypyrazole (3.60 g, 21.73 mmol)were added and the mixture was heated at 90° C. for 18 h. Work upyielded a crude red oil. Purification by Flash Chromatography (0-35%diethyl ether/hexane). Yield 58.47% yellow solid. ¹H NMR 400 MHz DMSO δ(ppm): 8.34 (s, 1H); 6.71 (s, 1H); 4.07 (m, 2H); 3.88 (d, 2H); 3.70 (s,3H); 3.27 (m, 2H); 2.72 (m, 1H); 1.94 (m, 2H); 1.62 (m, 2H); 1.18 (t,3H). LCMS (ESI) m/z 444.3 (M+H⁺, 100%)

Compound A31-[6-(4-Methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

Following the general procedure [method 1] compound A3 was obtained as ayellow solid (52%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m, 16H), 4.15 (q,2H), 7.55-7.58 (m, 2H), 7.62-7.66 (m, 1H), 7.88-7.92 (m, 2H), 7.95 (s,1H). Exact mass calculated for C₂₄H₃₂N₆O₆S 532.21, found 533.3 (MH⁺).

Compound A41-[6-(Benzo[1,2,5]oxadiazol-5-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

Following the general procedure, [method 1] compound A4 was obtained asa brown solid (65%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96(m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05 (m, 2H), 4.14(q, 2H), 7.22 (d, 1H), 7.60 (s, 1H), 7.82 (d, 1H), 8.16 (s, 1H). Exactmass calculated for C₁₈H₁₈N₆O₆ 414.13, found 415.3 (MH⁺).

Compound A51-{6-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester: [Method 1]

Flash chromatography (hexanes:ethyl acetate=2:1) provided compound A5 asa yellow solid (250 mg, 65%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.78-1.88 (m, 2H), 1.95-2.05 (m, 2H), 2.62-2.70 (m, 1H), 3.22 (t, 2H),3.76 (s, 2H), 4.00 (s, 3H), 4.02-4.08 (m, 2H), 4.18 (q, 2H), 7.25 (d,2H), 8.00 (d, 2H), 8.22 (s, 1H). Exact mass calculated for C₂₂H₂₄N₄O₈472.16, found 473.4 (MH⁺).

Compound A61-[5-Amino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester: General Method 4

A2 (100 mg, 0225 mmol) was dissolved in ethanol (8.0 ml), 5% Pd/C (0.1mmol) was added to the reaction vessel with stirring. The mixture waspurged with hydrogen and after 15 min the desired product A6 wasobserved by LCMS. Filtration followed by solvent removal under reducedpressure yielded a solid that was purified by filtration through asilica plug using 50% ethyl acetate/hexane as solvent. Yield 32.13%. ¹HNMR 400 MHz DMSO δ (ppm): 8.34 (s, 1H); 6.71 (s, 1H); 4.07 (m, 2H); 3.88(d, 2H); 3.70 (s, 2H); 3.30 (s, 3H); 3.23 (m, 2H); 2.72 (m, 1H); 1.95(m, 2H); 1.62 (m, 2H); 1.17 (t, 3H). LCMS (ESI) m/z 415.3 (M⁺H⁺, 100%)

Compound A71-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester General Method 5:

A6 (50 mg, 0.12 mmol) and diisopropylamine (0.83 ml, 0.476 mmol) weredissolved in anhydrous dichloromethane (2.0 ml), and excess (CF₃CO)₂Owas added dropwise at 0° C. Stirring at room temp. was maintained for 12hours. Purification by RP-HPLC. Yield 46% white solid. ¹H NMR 400 MHzDMSO δ (ppm): 8.36 (s, 1H); 6.73 (s, 1H); 4.06 (m, 2H); 3.89 (d, 2H);3.72 (s, 3H); 3.23 (m, 2H); 2.73 (m, 1H); 1.97 (m, 2H); 1.62 (m, 2H);1.17 (t, 3H). LCMS (ESI) m/z 511.3 (M⁺H⁺, 100%)

Compound A8 Propionic acid1-[2-amino-5-formyl-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidin-4-ylester General Method 6:

4,6-dichloro-2-amino-5-formylpyrimidine (1.90 g, 9.89 mmol) anddiisopropylethylamine (3.30 ml, 18.95 mmol) were dissolved in anhydrous1,4-dioxane (25.0 ml). The mixture was stirred on an ice bath and4-ethyl ester piperidine (1.46 ml, 9.47 mmol) dissolved in dioxane (25.0ml) was added dropwise. The mixture attained room temperature and after30 min. the desired product was observed by LCMS m/z 313 (M+H⁺). Thesolvent was removed under reduced pressure, and the crude residuedissolved in dioxane (20 ml), to it were added diisopropylethylamine(6.31 ml, 36.22 mmol) and 2-Methyl-5-trifluoromethyl-2H-pyrazol-3-ol(3.95 g, 23.77 mmol). The mixture heated at 90° C. for 18 h. Aqueouswork up yielded a pale orange solid. Recrystallization from ether andhexanes, followed by filtration of the solid yielded white crystals.Yield 50.28%, ¹H NMR 400 MHz DMSO δ (ppm): 9.90 (s, 1H); 7.42 (d, 2H);6.76 (s, 1H); 4.09 (m, 2H); 3.95 (d, 2H); 3.76 (s, 3H); 3.09 (m, 2H);2.63 (m, 1H); 1.90 (m, 2H); 1.66 (m, 2H); 1.19 (t, 3H). LCMS (ESI) m/z443 (M+H⁺, 100%)

Compound A94-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperazine-1-carboxylicacid ethyl ester

[method 3]. Purification by Flash Chromatography (5-30% ethylacetate/hexane). Yield 33% yellow oil. ¹H NMR 400 MHz DMSO δ (ppm): 8.38(s, 1H); 6.71 (s, 1H); 4.04 (m, 2H); 3.88 (d, 2H); 3.70 (s, 3H); 3.54(m, 2H); 3.42 (m, 2H); 3.29 (m, 2H) 1.18 (t, 3H). LCMS (ESI) m/z 446.2(M⁺H⁺, 100%)

Compound A101-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid methyl ester

[method 3]. Flash chromatography (hexanes:ethyl acetate=2:1) providedcompound A10 as a yellow solid (173 mg, 30%). ¹H NMR (CDCl₃, 400 MHz) δ1.80-1.88 (m, 2H), 2.02-2.12 (m, 2H), 2.72-2.74 (m, 1H), 3.72 (s, 3H),3.78 (s, 3H). 3.94-4.06 (m, 2H), 6.49 (s, 1H), 8.25 (s, 1H). Exact masscalculated for C₁₆H₁₇F₃N6O₅ 430.12, found 431.4 (MH⁺).

Compound A112,6-Dimethyl-4-[6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-morpholine

[method 3]. Purification by Flash Chromatography (0-30% ethylacetate/hexane).

Yield 57% yellow oil. ¹H NMR 400 MHz DMSO δ (ppm): 8.37 (s, 1H); 6.71(s, 1H); 3.83 (m, 2H); 3.72 (s, 3H); 3.62 (m, 2H); 2.81 (m, 2H); 1.12(t, 6H). LCMS (ESI) m/z 403 (M⁺H⁺, 100%)

Compound A121-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-3-carboxylicacid ethyl ester

[method 3]. Purification by Flash Chromatography (0-50% ethylacetate/hexane).

Yield 50% yellow oil. ¹H NMR 400 MHz DMSO δ (ppm): 8.36 (s, 1H); 6.72(s, 1H); 4.08 (m, 2H); 3.98 (m, 2H); 3.72 (s, 3H); 3.58 (m, 1H); 3.45(m, 1H); 2.69 (m, 1H); 1.99 (m, 1H); 1.76 (m, 2H); 1.57 (m, 1H); 1.17(t, 3H). LCMS (ESI) m/z 445 (M⁺H⁺, 100%)

Compound A131-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethylamide

[method 1]. Purification by HPLC. Yield 16%. ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.17 (s, 1H); 6.43 (s, 1H); 4.06 (m, 2H); 3.72 (s, 3H); 3.12 (m,2H); 2.58 (m, 3H); 1.88 (m, 4H). LCMS (ESI) m/z 416.1 (M+H⁺, 100%)

Compound A141-[6-(2-Methyl-5-phenyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1]. The product was purified by column chromatography on silica(Biotage) using hexane/ethyl acetate (7:3). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.23 (s, 1H, pyrimidine); 7.78 (d, 2H), 7.40-7.35 (dd, 2H), 6.50(s, 1H), 4.20 (q, 2H), 4.10-4.00 (m, 2H), 3.78 (s, 3H), 3.30-3.20 (m,2H), 2.70-2.60 (m, 1H), 2.10-2.00 (m, 2H), 2.95-2.80 (m, 2H), 1.30 (t,3H). LCMS (ESI) for C₂₂H₂₄N₆O₅: m/z 453.2 (M+H⁺, 100%)

Compound A154-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-piperidin-1-yl-pyrimidine

[method 3]. The product was purified by Preparatory TLC usinghexane/ethyl acetate (7:3). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.20 (s, 1H,pyrimidine); 6.45 (s, 1H); 3.80 (s, 3H, CH₃), 3.60-3.50 (m, 4H);1.75-1.60 (m, 5H). LCMS (ESI) for C₁₄H₁₅F₃N₆O₃: m/z 373 (M+H⁺, 100%)

Compound A161-[5-Nitro-6-(2-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester; General Method 7

1-(6-chloro-5-nitropyrimidine-4-yl)-piperidine-4-carboxylic acid ethylester 1 (0.22 g, 0.63 mmol) and 2-(trifluoromethanol) benzyl alcohol(0.11 g, 1.26 mmol) were dissolved in DMF at room temperature. Sodiumhydride (30 mg, 1.26 mmol) was added and the mixture was stirred at 40°C. for 30 minutes. Diluted the mixture with 10% aq. HCl, and extractedtwice with EtOAc. The combined organic extracts were washed with waterand brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by preparatory LCMS. ¹H NMR, 400 MHz, CDCl₃, δ(ppm): 8.20 (s, 1H); 7.63 (t, 2H); 7.55 (t, 1H); 7.39 (t, 1H); 5.63 (s,2H); 4.13 (q, 2H); 3.95 (d, 2H); 3.14 (t, 2H); 2.54 (m, 1H); 1.98 (m,2H); 1.79 (m, 2H); 1.24 (t, 3H). LCMS (ESI) for C₂₀H₂₁F₃N₄O₅: m/z 454(M+H⁺, 100%)

Compound A171-[5-Nitro-6-(3-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 7]. The residue was purified by preparatory TLC usinghexane/ethyl acetate (3/1, v/v). ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.22(s, 1H); 7.66 (s, 1H); 7.58 (t, 2H); 7.49 (t, 1H); 5.52 (s, 2H); 4.15(q, 2H); 3.62 (m, 2H); 3.15 (t, 2H); 2.60 (m, 1H); 2.00 (m, 2H); 1.80(m, 2H); 1.27 (t, 3H). LCMS (ESI) for C₂₁H₂₃F₃N₄O₅: m/z 469 (M+H⁺, 100%)

Compound A181-[5-Nitro-6-(4-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 7]. The residue was purified by preparatory TLC usinghexane/ethyl acetate (3/1, v/v). ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.20(s, 1H); 7.62 (d, 2H); 7.52 (d, 2H); 5.52 (s, 2H); 4.11 (q, 2H); 3.96(m, 2H); 3.15 (t, 2H); 2.58 (m, 1H); 2.01 (m, 2H); 1.81 (m, 2H); 1.25(t, 3H). LCMS (ESI) for C₂₀H₂₁F₃N₄O₅: m/z 454 (M+H⁺, 100%)

Compound A191-[5-Bromo-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester; General Method 8

A mixture of1-[6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester (150 mg, 0.37 mmol) and NBS (65 mg, 0.37 mmol) in DMF(3 ml) was stirred at 60° C. for 2 days. The mixture was quenched withsodium thiosulfate, and extracted with ethyl acetate. The combinedorganic layer was dried with anhydrous sodium sulfate and concentratedin vacuo. Flash chromatography (hexanes:ethyl acetate=3:1) providedcompound A19 as a white solid (100 mg, 57%). ¹HNMR (CDCl₃, 400 MHz) δ1.28 (t, 3H), 1.78-1.88 (m, 2H), 1.95-2.05 (m, 2H), 2.57-2.62 (m, 1H),3.17 (t, 2H), 3.81 (s, 3H), 4.18 (q, 2H), 4.22-4.33 (m, 2H), 6.41 (s,1H), 8.22 (s, 1H). Exact mass calculated for C₁₇H₁₉BrF₃N₅O₃ 477.06,found 478.0 (MH⁺).

Compound A201-[5-Acetylamino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester and Compound A211-[5-Diacetylamino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester General Method 9:

A mixture of compound A6 (100 mg, 0.24 mmol) and acetic anhydride (0.1ml, 1 mmol) in pyridine (5 ml) was heated to 60° C. for three days. Themixture was concentrated in vacuo. Flash chromatography (hexanes:ethylacetate=1:1) provided compound A20a (7 mg, 7%) and A20b (40 mg, 34%)both as a yellow oil. Compound A20a ¹HNMR (CDCl₃, 400 MHz) δ 1.33 (t,3H), 1.77-1.85 (m, 2H), 1.95-2.05 (m, 2H), 2.22 (s, 3H), 2.55-2.62 (m,1H), 3.16 (t, 2H), 3.76 (s, 3H), 4.06-4.22 (m, 4H), 6.24 (s, 1H), 6.50(s, 1H), 8.22 (s, 1H). Exact mass calculated for C₁₉H₂₄F₃N₆O₄ 456.17,found 457.2 (MH⁺). Compound A20b ¹H NMR (CDCl₃, 400 MHz) δ 1.25 (t, 3H),1.77-1.85 (m, 2H), 1.95-2.05 (m, 2H), 2.37 (s, 6H), 2.55-2.62 (m, 1H),3.18 (t, 2H), 3.66 (s, 3H), 4.06-4.22 (m, 4H), 6.24 (s, 1H), 6.31 (s,1H), 8.25 (s, 1H). Exact mass calculated for C₂₁H₂₅F₃N₆O₅ 498.18, found499.4 (M+H⁺).

Compound A221-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid

[method 3]. Purification of part of the crude by HPLC. Yield 8.58%yellow solid. ¹H NMR 400 MHz DMSO δ (ppm): 8.33 (s, 1H); 6.71 (s, 1H);3.88 (m, 2H); 3.70 (s, 3H); 3.22 (m, 2H); 2.63 (m, 1H); 1.93 (m, 2H);1.59 (m, 2H). LCMS (ESI) m/z 417 (M+H⁺, 100%)

Compound A231-{5-Nitro-6-[2-(2-trifluoromethyl-phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 7]. The residue was purified by preparatory TLC usinghexane/ethyl acetate (9/1, v/v). ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.63(s, 1H); 7.45 (m, 4H); 4.16 (q, 2H); 4.03 (m, 2H); 3.89 (t, 2H); 3.08(t, 2H); 3.20 (t, 2H); 2.55 (m, 1H); 2.03 (m, 2H); 1.80 (m, 2H); 1.28(t, 3H). LCMS (ESI) for C₂₁H₂₃F₃N₄O₅: m/z 468 (M+H⁺, 100%)

Compound A241-{5-Nitro-6-[2-(3-trifluoromethyl-phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 7]. The residue was purified by preparatory TLC usinghexane/ethyl acetate (9/1, v/v). ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.63(s, 1H); 7.45 (m, 4H); 4.16 (q, 2H); 4.03 (m, 2H); 3.89 (t, 2H); 3.08(t, 2H); 3.20 (t, 2H); 2.55 (m, 1H); 2.03 (m, 2H); 1.80 (m, 2H); 1.28(t, 3H). LCMS (ESI) for C₂₁H₂₃F₃N₄O₅: m/z 468 (M+H⁺, 100%)

Compound A251-[5-Di-(methanesulfonyl)amino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester; General Method 10

Compound A6 (150 mg, 0.36 mmol) was dissolved in dichloromethane (5 ml).To this was added DIEA (0.125 ml) and methane sulfonic anhydride (94 mg,0.54 mmol). The mixture was stirred at room temperature for 24 hours,quenched with water and extracted with dichloromethane. The combinedorganic layer was dried in vacuo and purified by HPLC to give compoundA25 as a yellow solid (24 mg, 12%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t,3H), 1.80-1.95 (m, 2H), 2.05-2.15 (m, 2H), 2.60-2.68 (m, 1H), 3.38 (t,2H), 3.50 (s, 6H), 3.79 (s, 3H), 4.17 (q, 2H), 4.44-4.55 (m, 2H), 6.24(s, 1H), 8.22 (s, 1H). Exact mass calculated for C₁₉H₂₃F₃N₆O₅S₂ 570.12,found 571.3 (MH⁺).

Compound A261-[5-Nitro-6-(3-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1]. The residue was purified by column chromatography (Biotage)using 10% hexane/ethyl acetate. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.16(s, 1H); 7.53 (m, 2H); 7.41 (s, 1H); 7.02 (d, 1H); 4.16 (q, 2H); 4.01(m, 1H); 3.21 (t, 2H); 2.97 (s, 9H); 2.90 (s, 9H); 2.63 (m, 1H); 2.02(m, 2H); 1.85 (m, 4H); 1.27 (t, 3H). LCMS (ESI) for C₁₉H₁₉F₃N₄O₅: m/z440 (M+H⁺, 100%)

Compound A271-[5-Methyl-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester; General Method 11

A mixture of A19 (100 mg, 0.21 mmol), methyl boronic acid (25 mg, 0.42mmol), dichlorobis(triphenylphosphine)palladium (II) (15 mg, 0.021 mmol)and potassium carbonate (87 mg, 0.62 mmol) in dry DMF (5 ml) was heatedto 100° C. under nitrogen overnight. The mixture was cooled to roomtemperature, quenched with water and extracted with ethyl acetate. Thecombined organic layer was dried with anhydrous sodium sulfate andconcentrated in vacuo. Flash chromatography (hexanes:ethyl acetate=3:1)provided compound A27 as an oil (20 mg, 23%). ¹HNMR (CDCl₃, 400 MHz) δ1.28 (t, 3H), 1.82-1.94 (m, 2H), 1.97-2.05 (m, 2H), 2.23 (s, 3H),2.57-2.62 (m, 1H), 3.02 (t, 2H), 3.77 (s, 3H), 3.82-3.88 (m, 2H), 4.18(q, 2H), 6.34 (s, 1H), 8.22 (s, 1H). Exact mass calculated forC₁₈H₂₂F₃N₅O₃ 413.17, found 414.4 (MH⁺).

Compound A281-[5-Nitro-6-(2-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1]. The residue was purified by column chromatography (Biotage)using 10% hexane/ethyl acetate. Yield 74%. ¹H NMR, 400 MHz, CDCl₃, δ(ppm): 8.14 (s, 1H); 7.70 (d, 1H); 7.62 (t, 1H); 7.38 (t, 1H); 7.26 (d,1H); 4.17 (q, 2H); 4.03 (m, 2H); 3.23 (t, 2H); 2.63 (m, 1H); 2.04 (m,2H); 1.85 (m, 2H); 1.28 (t, 3H). LCMS (ESI) for C₁₉H₁₉F₃N₄O₅: m/z 440(M+H⁺, 100%)

Compound A291-{1-[5-Nitro-6-(4-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-carboxylicacid ethyl ester

[method 1]. The residue was purified by column chromatography (Biotage)using 10% hexane/ethyl acetate. Yield 58%. ¹H NMR, 400 MHz, CDCl₃, δ(ppm): 8.01 (s, 1H); 7.47 (d, 2H); 6.93 (d, 2H); 4.16 (q, 2H); 4.05 (m,2H); 3.23 (t, 2H); 2.66 (m, 1H); 2.09 (m, 2H); 1.93 (m, 2H); 1.28 (t,3H). LCMS (ESI) for C₁₉H₁₉₁F₃N₄O₅: m/z 440 (M+H⁺, 100%)

Compound A301-[6-(4-Fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1]. Yield 0.016 g, 16%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 8.17 (s, 1H); 7.10 (m, 4H); 4.18 (q, 2H); 4.03 (m, 2H); 3.22 (m,2H); 2.63 (m 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.29 (m, 3H). LCMS (ESI)m/z 391 (M+H⁺, 100%)

Compound A311-[6-(2,5-Dimethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 3]. The product was purified by column chromatography on silica(Biotage) using hexane/ethyl acetate (7:3). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.23 (s, 1H, pyrimidine); 5.97 (s, 1H), 4.20 (q, 2H), 4.10-4.00(m, 2H), 3.50 (s, 3H), 3.30-3.20 (m, 2H), 2.70-2.60 (m, 1H), 2.10 (s,3H), 2.00 (m, 2H), 1.95-1.90 (m, 2H), 1.30 (t, 3H). LCMS (ESI) forC₁₇H₂₂N₆O₅: m/z 391.3 (M+H⁺, 100%)

Compound A321-[6-(4-Bromo-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1]. The solvent was removed in vacuo and the residue purified bypreparatory thin layer chromatography [SiO₂; EtOAc/hexane; 50:50]. Yield0.010 g, 9%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□ (ppm): 8.17 (s, 1H);7.52 (d, 2H); 7.03 (d, 2H); 4.17 (q, 2H); 4.02 (m, 2H); 3.22 (m, 2H);2.63 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.29 (m, 3H)

LCMS (ESI) m/z 452, 453 (M+H⁺, 100%)

Compound A331-[6-(4-Chloro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1]. Yield 0.009 g, 9%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 8.17 (s, 1H); 7.37 (d, 2H); 7.08 (d, 2H); 4.17 (m, 2H); 4.03 (m,2H); 3.22 (m, 2H); 2.64 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.29 (m,3H). LCMS (ESI) m/z 407 (M+H⁺, 100%)

Compound A341-[6-(4-Carbamoyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

General Method 1a: A mixture of compound 7 (63 mg, 0.2 mmol),4-hydroxybenzene carboxamide (35 mg, 0.26 mmol) and potassium carbonate(36 mg, 0.26 mmol) in DMF (1 ml) was heated in microwave for 2 minutesat 80° C. Following the general procedure, compound A34 was obtained asa yellow solid (65%). ¹HNMR (CDCl₃, 400 MHz) δ 1.19 (t, 3H), 1.70-1.80(m, 2H), 1.98-2.03 (m, 2H), 2.65-2.80 (m, 1H), 3.22 (t, 2H), 3.82-3.96(m, 2H), 4.07 (q, 2H), 7.25 (d, 2H), 7.40 (s, 1H), 7.92 (d, 2H), 8.00(s, 1H), 8.20 (s, 1H). Exact mass calculated for C₁₉H₂₁N₅O₆ 415.15,found 416.2 (MH⁺).

Compound A351-{6-[4-(2-Methoxy-ethyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A35 was obtainedas a yellow solid (71%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.70-1.80 (m, 2H), 1.98-2.03 (m, 2H), 2.65-2.75 (m, 1H), 2.94 (t, 2H),3.22 (t, 2H), 3.37 (s, 3H), 3.62 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q,2H), 7.05 (d, 2H), 7.25 (d, 2H), 8.17 (s, 1H). Exact mass calculated forC₂₁H₂₆N₄O₆ 430.19, found 431.4 (MH⁺).

Compound A361-[6-(4-Cyclopentyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A36 was obtainedas a yellow solid (58%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.58-1.92 (m, 8H), 1.98-2.15 (m, 4H), 2.65-2.75 (m, 1H), 3.00 (quintet,1H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.04 (d, 2H), 7.25(d, 2H), 8.18 (s, 1H). Exact mass calculated for C₂₃H₂₈N₄O₅ 440.21,found 441.2 (MH⁺).

Compound A371-[5-Nitro-6-(4-pyrrol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A37 was obtainedas a yellow solid (77%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H),3.96-4.03 (m, 2H), 4.15 (q, 2H), 6.36 (d, 2H), 7.04 (d, 2H), 7.19 (d,2H), 7.40 (d, 2H), 8.18 (s, 1H). Exact mass calculated for C₂₂H₂₃N₅O₅437.17, found 438.2 (MH⁺).

Compound A38

1-[6-(4-Benzoyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A38 was obtainedas a yellow solid (70%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H),3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.24-7.28 (m, 2H), 7.46-7.51 (m, 2H),7.58-7.62 (m, 1H), 7.78-7.82 (m, 2H), 7.87-7.90 (m, 2H), 8.21 (s, 1H).Exact mass calculated for C₂₅H₂₄N₄O₆ 476.17, found 477.2 (MH⁺).

Compound A391-{6-[4-(4-Hydroxy-benzenesulfonyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A39 was obtainedas a yellow solid (51%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H),3.96-4.03 (m, 2H), 4.15 (q, 2H), 6.82 (d, 2H), 7.25 (d, 2H), 7.78 (d,2H), 7.96 (d, 2H), 8.13 (s, 1H). Exact mass calculated for C₂₄H₂₄N₄O₈S528.13, found 529.2 (MH⁺).

Compound A401-[6-(4′-Cyano-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A40 was obtainedas a yellow solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (m,2H), 4.15 (q, 2H), 7.24-7.26 (m, 2H), 7.61-7.78 (m, 6H), 8.19 (s, 1H).Exact mass calculated for C₂₅H₂₃N₅O₅ 473.17, found 473.3 (MH⁺).

Compound A411-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A41 was obtainedas a yellow solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.14 (q, 2H), 3.40 (t, 2H),3.96-4.03 (m, 2H), 4.18 (q, 2H), 7.18 (d, 2H), 7.68 (d, 1H), 7.72 (d,1H), 8.06 (s, 1H), 10.35 (s, 21-1). Exact mass calculated forC₂₀H₂₅N₅O₇S 479.15, found 480.0 (MH⁺).

Compound A421-{6-[4-(5-Hydroxy-pyrimidin-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A42 was obtainedas a yellow solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.14 (q, 2H), 3.40 (t, 2H),3.96-4.03 (m, 2H), 4.18 (q, 2H), 7.36 (d, 2H), 8.20 (s, 1H), 8.38 (d,2H), 8.77 (s, 2H). Exact mass calculated for C₂₂H₂₂N₆O₆ 466.16, found467.2 (MH⁺).

Compound A431-[5-Nitro-6-(4-sulfo-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

-   [method 1a]. Following the general procedure, compound A43 was    obtained as a yellow solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),    1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.14 (q,    2H), 3.40 (t, 2H), 3.70-3.82 (m, 2H), 4.05 (q, 2H), 7.12 (d, 2H),    7.60 (d, 2H), 8.20 (s, 1H). Exact mass calculated for C₁₈H₁₉N₄O₈SNa    474.08, found 475 (M+H⁺).

Compound A441-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A44 was obtainedas a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (m,2H), 4.15 (q, 2H), 7.33 (d, 2H), 7.73 (d, 2H), 8.17 (s, 2H), 8.69 (s,1H). Exact mass calculated for C₂₀H₂₁N₇O₅ 439.16, found 440.4 (MH⁺).

Compound A451-[6-(4-Carbamoylmethyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A45 was obtainedas a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.60 (s, 2H),3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.17 (d, 2H), 7.38 (d, 2H), 8.17 (s,1H). Exact mass calculated for C₂₀H₂₃N₅O₆ 429.16, found 430.3 (MH⁺).

Compound A461-{6-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound a46 was obtainedas a yellow solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.60 (s, 2H),3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.26-7.29 (m, 2H), 7.52-7.55 (m, 2H),7.82 (dd, 2H), 7.94 (dd, 2H), 8.19 (s, 1H). Exact mass calculated forC₂₆H₂₃N₅O₇ 517.16, found 518.3 (MH⁺).

Compound A471-[6-(4′-Methoxy-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A47 was obtainedas a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.60 (s, 2H),3.85 (s, 3H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 6.96 (d, 2H), 7.17 (d,2H), 7.54 (d, 2H), 7.60 (d, 2H), 8.17 (s, 1H). Exact mass calculated forC₂₅H₂₆N₄O₆ 478.19, found 479.2 (MH⁺).

Compound A481-{6-[4-(2,5-Dioxo-imidazolidin-4-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A48 was obtainedas a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.60 (s, 2H),3.96-4.03 (m, 2H), 4.15 (q, 2H), 5.16 (s, 1H), 5.30 (s, 1H), 5.60 (s,1H), 7.26 (d, 2H), 7.43 (d, 2H), 8.16 (s, 1H). Exact mass calculated forC₂₁H₂₂N₆O₇ 470.15, found 471.1 (MH⁺).

Compound A494-(4,4-Difluoro-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine

[method 2 followed by method 3]. Purification by HPLC yielded a yellowsolid.

Yield 54.71%. 1H NMR 400 MHz CDCl₃ δ (ppm): 8.29 (s, 1H); 6.52 (s, 1H);3.80 (s, 3H); 3.71 (m, 2H); 2.11 (m, 2H); 2.01 (m, 4H). LCMS (ESI) m/z409.2 (M⁺H⁺, 100%)

Compound A501-{5-Nitro-6-[4-(4-oxo-cyclohexyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

-   [method 1a]. Following the general procedure, compound A50 was    obtained as a yellow solid (45%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t,    3H), 1.80-2.05 (m, 6H), 2.21-2.24 (m, 2H), 2.52-2.56 (m, 2H),    2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.60 (s, 2H), 3.96-4.03 (m, 2H),    4.15 (q, 2H), 7.10 (d, 2H), 7.26 (d, 2H), 8.17 (s, 1H). Exact mass    calculated for C₂₄H₂₈₃N₄O₆ 468.2, found 469.2 (MH⁺).

Compound A511-{5-Nitro-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

-   [method 1a]. Following the general procedure, compound A51 was    obtained as a yellow solid (61%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t,    3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.16 (s, 3H), 2.65-2.75    (m, 1H), 2.72-2.78 (m, 2H), 2.82-2.90 (m, 2H), 3.22 (t, 2H), 3.60    (s, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.02 (d, 2H), 7.22 (d,    2H), 8.17 (s, 1H). Exact mass calculated for C₂₂H₂₆N₄O₆ 442.19,    found 443.0 (MH⁺).

Compound A521-[5-Nitro-6-(4-propionyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A52 was obtainedas a yellow solid (70%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.01 (q, 2H),3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.21 (d, 2H), 8.02 (d,2H), 8.17 (s, 2H). Exact mass calculated for C₂₁H₂₄N₄O₆ 428.17, found429.3 (MH⁺).

Compound A531-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A53 was obtainedas a yellow solid (57%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H),3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.28 (d, 2H), 8.10 (d, 2H), 8.19 (s,1H), 8.64 (s, 1H). Exact mass calculated for C₂₀H₂₀N₆O₄S 456.12, found457.2 (MH⁺).

Compound A541-{6-[4-(2-Hydroxy-ethyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A54 was obtainedas a yellow solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 2.88 (t, 2H), 3.05 (t, 0.5H),3.22 (t, 2H), 3.87 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 4.55 (t,0.5H), 7.07 (d, 2H), 7.22 (d, 2H), 8.15 (s, 1H). Exact mass calculatedfor C₂₀H₂₄N₄O₆ 416.17, found 417.3 (MH⁺).

Compound A55{4-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone

General Procedure 2 followed by method 1a. Flash column chromatography[Hexane:Ethyl Acetate=1:1] provided the intermediate as a yellow oil(444 mg, 84%). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.40 (s, 1H); 3.70 (sb, 4H);2.1 (t, 4H). Exact mass calculated for C₉H₉ClF₂N₄O₂ 278.04, LCMS (ESI)m/z 279.3 (M+H⁺, 100%).

[method 1a]. HPLC provided compound A55 as yellow solid (26 mg, 59%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 8.25 (s, 1H); 7.90 (dd, 2H); 7.80 (dd, 2H);7.61 (td, 1H); 7.50 (td, 2H); 7.26 (d, 2H); 3.75 (sb, 4H); 2.15 (qu,4H). Exact mass calculated for C₂₂H₁₈F₂N₄O₄ 440.13, LCMS (ESI) m/z 441.3(M+H⁺, 100%).

Compound A563-{4-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionicacid methyl ester

[method 1a]. HPLC provided compound A56 as yellow solid (10 mg, 24%).

¹H NMR 400 MHz CDCl₃ δ(ppm): 8.21 (s, 1H); 8.04 (d, 2H); 7.24 (d, 2H);4.01 (s, 2H); 3.75 (sb, 4H); 2.15 (q, 4H); 2.00 (sb, 3H). Exact masscalculated for C₁₉H₁₈F₂N₄O₆ 436.12, LCMS (ESI) m/z 437.3 (M+H⁺, 100%).

Compound A572-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-5-ethanesulfonyl-phenylamine

[method 1a]. HPLC provided compound A57 as yellow oil (31 mg, 70%). ¹HNMR 400 MHz CDCl₃ δ (ppm): 10.35 (s, 1H); 8.18 (s, 1H); 7.85 (s, 1H);7.63 (d, 1H); 7.19 (d, 1H); 3.78 (s, 4H); 3.16 (q, 2H); 2.20 (q, 4H);1.21 (sb, 3H). Exact mass calculated for C₁₇H₁₉F₂N₅O₅S 443.11, LCMS(ESI) m/z 444.3 (M+H⁺, 100%).

Compound A584-(4-Cyclopentyl-phenoxy)-6-(4,4-difluoro-piperidin-1-yl)-5-nitro-pyrimidine

[method 1a]. HPLC provided compound A58 as yellow solid (20 mg, 50%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 8.21 (s, 1H); 7.25 (d, 2H); 7.06 (d, 2H); 3.70(s, 4H); 3.03 (q, 1H); 2.10 (sb, 4h); 1.80 (d, 2H); 1.71 (t, 2H); 1.60(sb, 4H). Exact mass calculated for C₂₀H₂₂F₂N₄O₃ 404.17, LCMS (ESI) m/z405.2 (M+H⁺, 100%).

Compound A591-[6-(2,6-Dichloro-4-methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A59 was obtainedas a yellow solid (52%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m,16H), 4.15 (q, 2H), 7.55-7.58 (m, 2H), 7.62-7.66 (m, 1H), 7.88-7.92 (m,2H), 7.95 (s, 1H). Exact mass calculated for C₂₄H₃₂N₆O₆S 532.21, found533.3 (MH⁺).

Compound A601-{6-[4-(4-Chloro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A60 was obtainedas a yellow solid (52%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m,16H), 4.15 (q, 2H), 7.55-7.58 (m, 2H), 7.62-7.66 (m, 1H), 7.88-7.92 (m,2H), 7.95 (s, 1H). Exact mass calculated for C₂₄H₃₂N₆O₆S 532.21, found533.3 (MH⁺).

Compound A611-{6-[4-(4-Hydroxy-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A61 was obtainedas a yellow solid (52%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m,16H), 4.15 (q, 2H), 7.55-7.58 (m, 2H), 7.62-7.66 (m, 1H), 7.88-7.92 (m,2H), 7.95 (s, 1H). Exact mass calculated for C₂₄H₃₂N₆O₆S 532.21, found533.3 (MH⁺).

Compound A621-[6-(4-Cyanomethyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A62 was obtainedas a yellow solid (52%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m,16H), 4.15 (q, 2H), 7.55-7.58 (m, 2H), 7.62-7.66 (m, 1H), 7.88-7.92 (m,2H), 7.95 (s, 1H). Exact mass calculated for C₂₄H₃₂N₆O₆S 532.21, found533.3 (MH⁺).

Compound A63(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone

General Procedure 2 followed by method 1a. Flash column chromatography[Methanol:Dichloromethane=1:9] provided the intermediate monochlorocompound as red oil (124 mg, 35%). Exact mass calculated forC₁₁H₁₆ClN₃O₄S 349.06, LCMS (ESI) m/z 350.1 (M+H⁺, 100%). [method 1a].Flash column chromatography [Hexane:Ethyl Acetate=2:1 thenMethanol:Dichloromethane=1:9] provided compound A63 as yellow oil (7 mg,14%). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.13 (d, 2H); 7.91 (d, 2H); 7.80 (d,2H); 7.60 (d, 1H); 7.50 (d, 2H); 7.21 (t, 1H); 4.03 (m, 2H); 3.71 (db,6H); 3.31 (sb, 2H); 3.08 (s, 3H); 3.00 (s, 2H). Exact mass calculatedfor C₂₄H₂₅N₅O₆S 511.15, LCMS (ESI) m/z 512.1 (M+H⁺, 100%).

Compound A644-(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one

[method 1a]. Flash column chromatography [Hexane:Ethyl Acetate=2:1 thenMethanol:Dichloromethane=1:9] provided compound A64 as yellow oil (6 mg,13%). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.20 (s, 1H); 7.21 (d, 2H); 7.05 (d,2H); 3.63 (s, 4H); 3.20 (d, 2H); 3.03 (s, 3H); 2.90 (m, 4H); 2.80 (t,2H); 2.61 (sb, 4H); 2.18 (s, 3H). Exact mass calculated for C₂₁H₂₇N₅O₆S477.17, LCMS (ESI) m/z 478.1 (M+H⁺, 100%).

Compound A653-(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-3-oxo-propionicacid methyl ester

[method 1a]. Flash column chromatography [Hexane:Ethyl Acetate=2:1 thenMethanol:Dichloromethane=1:9] provided compound A65 as yellow oil (7 mg,14%). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.20 (s, 1H); 8.02 (d, 2H); 7.26 (d,2H); 4.01 (d, 2H); 3.73 (s, 7H); 3.10 (sb, 5H). Exact mass calculatedfor C₂₁H₂₅N₅O₈S 507.14, LCMS (ESI) m/z 508.2 (M+H⁺, 100%).

Compound A664-(4-Methyl-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine

[method 2 followed by general method 3]. Purification by HPLC yieldedA66 as a yellow solid. Yield: 18%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.10(s, 1H); 6.36 (s, 1H); 3.95 (d, 2H); 3.65 (s, 3H); 2.93 (m, 2H); 1.62(m, 3H); 1.14 (m, 2H); 0.85 (m, 3H). LCMS (ESI) m/z 387 (M⁺H⁺, 100%)

Compound A674-(4-Bromo-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine

[method 2 followed by general method 3]. Final purification by HPLCyielded an orange solid. Yield 22%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.31(s, 1H); 6.51 (s, 1H); 4.41 (m, 1H); 3.84 (m, 2H); 3.81 (s, 3H); 3.66(m, 2H); 2.17 (m, 2H); 1.98 (m, 2H). LCMS (ESI) m/z 453 (M⁺H⁺, 100%)

Compound A684-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine

[method 1a]. provided compound A68 as yellow solid (501 mg, 55% yield).¹H NMR 400 MHz CDCl₃ δ (ppm): 8.25 (s, 1H); 6.51 (s, 1H); 4.13 (dt, 2H);3.80 (s, 3H); 3.07 (td, 2H); 1.82 (d, 2H); 1.63-1.56 (m, 1H); 1.40-1.22(m, 6H); 0.93 (t, 3H). Exact mass calculated for C₁₇H₂₁F₃N₆O₃ 414.16,LCMS (ESI) m/z 415.3 (M+H⁺, 100%).

Compound A691-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid amide

[method 3]. Purification by HPLC yielded a yellow solid. Yield 16%. ¹HNMR 400 MHz CDCl₃ δ (ppm): 8.17 (s, 1H); 6.43 (s, 1H); 4.06 (m, 2H);3.72 (s, 3H); 3.12 (m, 2H); 2.58 (m, 3H); 1.88 (m, 4H). LCMS (ESI) m/z416.1 (M+H⁺, 100%)

Compound A701-[5-Nitro-6-(2-oxo-2H-chromen-6-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A70 was obtainedas a yellow solid (43%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05 (m,2H), 4.14 (q, 2H), 6.38 (d, 1H), 7.02 (d, 1H), 7.10 (s, 1H), 7.42 (d,1H), 7.63 (d, 1H), 8.13 (s, 1H). Exact mass calculated for C₂₁H₂₀N₄O₇440.13, found 441.3 (MH⁺).

Compound A711-[5-Nitro-6-(2-oxo-benzo[1,3]oxathiol-6-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A71 was obtainedas a yellow solid (34%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05 (m,2H), 4.14 (q, 2H), 7.02 (d, 1H), 7.15 (s, 1H), 7.40 (d, 1H), 8.14 (s,1H). Exact mass calculated for C₁₉H₁₈N₄O₇S 446.09, found 447.0 (MH⁺).

Compound A721-[6-(9H-Carbazol-2-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A72 was obtainedas a yellow solid (89%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05 (m,2H), 4.14 (q, 2H), 6.90 (d, 1H), 7.00 (d, 1H), 7.03-7.08 (m, 1H),7.30-7.36 (m, 2H), 7.78-7.82 (m, 2H), 8.12 (s, 1H), 8.26 (s, 1H). Exactmass calculated for C₂₄H₂₃N₅O₅ 461.17, found 462.3 (MH⁺).

Compound A731-[5-Nitro-6-(9-oxo-9H-fluoren-2-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A73 was obtainedas a yellow solid (84%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05 (m,2H), 4.14 (q, 2H), 7.20-7.25 (m, 3H), 7.40-7.60 (m, 4H), 8.16 (s, 1H).Exact mass calculated for C₂₅H₂₂N₄O₆ 474.15, found 475.1 (MH⁺).

Compound A741-{5-Amino-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester General Method 12:

A51 (348 mg, 0.786 mmol) was dissolved in ethyl acetate (10 mL),palladium on activated carbon (10 wt—degussa type) was added and themixture purged with H₂. The reaction was monitored by LCMS and aftercompletion the crude was filtered through celite and activated carbon.Purification by HPLC afforded Compound A74 as a light yellow oil. Yield:26%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.14 (s, 1H); 7.26 (d, 2H); 7.05 (d,2H); 6.38 (s, 2H); 4.19 (m, 2H); 3.88 (d, 2H); 3.17 (m, 2H); 2.94 (m,2H); 2.81 (m, 2H); 2.63 (m, 1H); 2.18 (s, 3H); 2.14 (d, 2H); 1.91 (m,2H); 1.30 (t, 3H). LCMS (ESI) m/z 413.4 (M⁺H⁺, 100%).

Compound A751-[6-[4-(3-Oxo-butyl)-phenoxy]-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester General Method 13:

A74 (61 mg, 0.148 mmol) and diisopropylethylamine (84 ml, 0.484 mmol)were dissolved in dichloromethane and trifluoroacetic anhydride (0.51ml, 0.363 mmol) was added. The mixture was stirred at room temperaturefor 3 hours and LCMS indicated the desired product. Purification by HPLCyielded light yellow oil. Yield 72.97%. ¹H NMR 400 MHz CDCl₃ δ (ppm):8.21 (s, 1H); 8.14 (s, 1H); 7.20 (d, 2H); 7.00 (d, 2H); 4.15 (m, 4H);3.13 (m, 2H); 2.89 (m, 2H); 2.77 (m, 2H); 2.57 (m, 2H); 2.15 (s, 3H);1.99 (m, 2H); 1.77 (m, 2H); 1.26 (t, 3H). LCMS (ESI) m/z 509.2 (M+H⁺,100%)

Compound A761-{5-Amino-6-[4-(hydroxy-phenyl-methyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 12]. Purification by HPLC yielded oil. Yield 8%. ¹H NMR 400 MHzCDCl₃ δ (ppm): 8.05 (s, 1H); 7.38 (m, 8H); 7.12 (d, 2H); 5.86 (s, 1H);4.18 (m, 2H); 3.99 (s, 2H); 3.80 (d, 2H); 2.94 (m, 2H); 2.55 (m, 1H);2.09 (m, 2H); 1.88 (m, 2H); 1.29 (t, 3H). LCMS (ESI) m/z 449.3 (M⁺H⁺,100%)

Compound A771-[6-(2-Benzoyl-5-methoxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A77 was obtainedas a yellow solid (52%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m,16H), 4.15 (q, 2H), 7.55-7.58 (m, 2H), 7.62-7.66 (m, 1H), 7.88-7.92 (m,2H), 7.95 (s, 1H). Exact mass calculated for C₂₄H₃₂N₆O₆S 532.21, found533.3 (MH⁺).

Compound A781-[6-(6-Chloro-pyridin-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. HPLC provided compound A78 as yellow solid (63 mg, 61%). ¹HNMR 400 MHz CDCl₃ δ (ppm): 8.20 (d, 1H); 8.08 (s, 1H); 7.43 (dd, 1H);7.30 (d, 1H); 4.09 (q, 2H); 3.95 (dt, 2H); 3.15 (td, 2H); 2.55 (m, 1H);1.95 (dt, 2H); 1.77 (td, 2H); 1.19 (t, 31-1). Exact mass calculated forC₁₇H₁₈ClN₅O₅ 407.10, LCMS (ESI) m/z 408.3 (M+H⁺, 100%).

Compound A791-[6-(Benzo[1,3]dioxol-5-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A79 was obtainedas an oil (46%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05 (m, 2H), 4.14 (q,2H), 6.00 (s, 2H), 6.57 (d, 1H), 6.60 (s, 1H), 6.80 (d, 1H), 8.16 (s,1H). Exact mass calculated for C₁₉H₂₀N₄O₇ 416.13, found 417.0 (MH⁺).

Compound A801-[6-(4-Benzyloxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A80 was obtainedas a yellow solid (25%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05 (m,2H), 4.14 (q, 2H), 5.04 (s, 2H), 6.94-7.05 (m, 4H), 7.27-7.41 (m, 5H),8.19 (s, 1H). Exact mass calculated for C₂₅H₂₆N₄O₆ 478.19, found 479.1(MH⁺).

Compound A811-[6-(3-Morpholin-4-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A81 was obtainedas an oil (84%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.80-1.96 (m,2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.20-3.35 (m, 6H), 3.82-3.84(m, 2H), 3.98-4.05 (m, 2H), 4.14 (q, 2H), 6.75-6.80 (m, 2H), 6.95-6.99(m, 1H), 7.32-7.38 (m, 1H), 8.17 (s, 1H). Exact mass calculated forC₂₂H₂₇N₅O₆ 457.20, found 458.3 (MH⁺).

Compound A821-[5-Nitro-6-(4-trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A82 was obtainedas a yellow solid (32%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05 (m,2H), 4.14 (q, 2H), 7.26 (d, 2H), 7.68 (d, 2H), 8.17 (s, 1H). Exact masscalculated for C₁₉H₁₉F₃N₄O₅S 472.1, found 473.1 (MH⁺).

Compound A831-[5-Nitro-6-(4-trifluoromethoxy-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Following the general procedure, compound A83 was obtainedas a yellow solid (79%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05 (m,2H), 4.14 (q, 2H), 7.18 (d, 2H), 7.26 (d, 2H), 8.17 (s, 1H). Exact masscalculated for C₁₉H₁₉F₃N₄O₆ 456.13, found 457.1 (MH⁺).

Compound A841-[6-(4-Benzoyl-phenoxy)-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 13]. Purification by HPLC. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.20(s, 1H); 7.97 (s, 1H); 7.79 (d, 2H); 7.72 (d, 2H); 7.52 (m, 1H); 7.41(m, 2H); 7.13 (d, 2H); 4.09 (m, 4H); 3.11 (m, 2H); 2.53 (m, 1H); 1.94(m, 2H); 1.72 (m, 2H); 1.19 (t, 3H). LCMS (ESI) m/z 543.5 (M+H⁺, 100%)

Compound A85{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-phenyl-methanoneGeneral Procedure 2 Followed by Method 3.

Intermediate: ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.26 (s, 1H); 4.035 (d, 2H);2.94 (td, 2H); 1.73 (dt, 2H); 1.50 (m, 1H); 1.27 (m, 2H); 1.18 (m, 2H);1.12 (dd, 2H); 0.84 (t, 3H). Exact mass calculated for C₁₂H₁₇ClN₃O₂284.10, LCMS (ESI) m/z 285.0 (M+H⁺, 100%).

[method 1]. HPLC provided compound A85 as yellow oil (77 mg, 69% yield).¹H NMR 400 MHz CDCl₃ δ (ppm): 8.01 (s, 1H); 7.71 (dd, 2H); 7.62 (dd,2H); 7.41 (tt, 1H); 7.30 (dt, 2H); 7.07 (dt, 3H); 3.92 (d, 2H); 2.86(td, 2H); 1.62 (dd, 2H); 1.39 (m, 1H); 1.14 (dt, 2H); 1.06 (t, 2H); 1.06(q, 2H); 0.72 (t, 3H). Exact mass calculated for C₂₅H₂₆N₄O₄ 446.20, LCMS(ESI) m/z 447.2 (M+H⁺, 100%).

Compound A86{4-Methoxy-2-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone

[method 1]. HPLC provided compound A86 as orange oil (67 mg, 57% yield).

¹H NMR 400 MHz CDCl₃ δ(ppm): 7.88 (s, 1H); 7.50 (dd, 2H); 7.40 (s, 1H);7.37 (tt, 1H); 7.30 (t, 1H); 7.22 (t, 2H); 6.71 (dd, 1H); 6.625 (d, 1H);3.81 (d, 2H); 3.71 (s, 3H); 2.81 (td, 2H); 1.58 (dd, 2H); 1.36 (m, 1H);1.16 (dt, 2H); 1.06 (td, 2H); 1.01 (dd, 2H); 0.73 (t, 3H). Exact masscalculated for C₂₆H₂₈N₄O₅ 476.21, LCMS (ESI) m/z 476.9 (M+H⁺, 100%).

Compound A874-{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2-one

[method 1]. HPLC provided compound A87 as yellow solid (62 mg, 59%yield). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.08 (s, 1H); 7.13 (d, 2H); 6.95(d, 2H); 4.00 (d, 2H); 2.96 (td, 2H); 2.82 (t, 2H); 2.69 (t, 2H); 2.07(s, 3H); 1.71 (dd, 2H); 1.48 (m, 1H); 1.27 (m, 2H); 1.17 (m, 4H); 0.83(t, 3H). Exact mass calculated for C₂₂H₂₈N₄O₄ 412.21, LCMS (ESI) m/z413.4 (M+H⁺, 100%).

Compound A885-Nitro-4-(4-propyl-piperidin-1-yl)-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine

[method 1]. HPLC provided compound A88 as yellow solid (61 mg, 56%yield). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.56 (s, 1H); 8.11 (s, 1H); 8.02(d, 2H); 7.22 (d, 2H); 4.03 (d, 2H); 2.96 (td, 2H); 1.73 (dd, 2H); 1.48(m, 1H); 1.27 (m, 2H); 1.2 (m, 4H); 0.84 (t, 3H). Exact mass calculatedfor C₂₀H₂₂N₆O₃S 426.15, LCMS (ESI) m/z 427.1 (M+H⁺, 100%).

Compound A893-{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionicacid methyl ester

[method 1]. HPLC provided compound A89 and A89a [enol] as yellow solid(12 mg, 4 mg, 18% yield). ¹H NMR 400 MHz CDCl₃ δ (ppm): A89: 8.08 (s,1H); 7.94 (d, 2H); 7.18 (d, 2H); 4.02 (d, 2H); 3.92 (s, 2H); 3.68 (s,3H); 2.96 (td, 2H); 1.72 (dd, 2H); 1.50 (m, 1H); 1.26 (m, 2H); 1.17 (m,4H); 0.83 (t, 3H). A89a: 8.08 (s, 1H); 7.94 (d, 2H); 7.75 (dd, 2H); 7.12(dd, 2H); 5.57 (s, 1H); 4.02 (d, 2H); 3.73 (s, 3H); 2.96 (1,2H); 1.72(d, 2H); 1.51 (m, 1H); 1.26 (m, 2H); 1.18 (m, 4H); 0.83 (t, 3H). Exactmass calculated for C₂₂H₂₆N₄O₆ 442.19, LCMS (ESI) m/z 443.3 (M+H⁺,100%).

Compound A905-Ethanesulfonyl-2-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenylamine

[method 1]. HPLC provided compound A92 as yellow solid (60 mg, 53%yield). ¹H NMR 400 MHz CDCl₃ δ (ppm): 10.2 (s, 1H); 7.97 (s, 1H); 7.63(d, 1H); 7.61 (s, 1H); 7.11 (d, 1H); 3.13 (td, 2H); 3.04 (q, 2H); 1.81(d, 2H); 1.59 (m, 1H); 1.28 (m, 2H); 1.2 (m, 4H); 0.84 (t, 3H). Exactmass calculated for C₂₀H₂₇N₅O₅S 449.17, LCMS (ESI) m/z 450.3 (M+H⁺,100%).

Compound A914-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine-5-carbonitrile

4,6-Dichloro-pyrimidine-5-carbonitrile (254 mg, 1.47 mmol) was dissolvedin DMF (3 mL). K₂CO₃ (203 mg, 1.47 mmol) and phenoxy methyl sulfone (253mg, 1.47 mmol) were added to the solution at 0° C. The reaction wasstirred for 30 min. The completion of the reaction was judged with TLC(EtOAc:Hex=1:1, R_(f)=0.82). After the completion of the reaction, wereadded the oxodiimidazol (340 mg, 1.47 mmol) and K₂CO₃ (406 mg, 2.94mmol) to the reaction at 0° C. The reaction was warmed to rt and stirredfor 30 min. The reaction was heated to 40° C. and maintained for 1 h.The reaction was cooled to rt, poured in to H₂O (50 mL) and extractedwith EtOAc (50 mL, two times). The EtOAc was dried over MgSO₂ andconcentrated under vacuum. The crude product was purified over SiO₂(EtOAc:Hex=1:1, R_(f)=0.39) to afford the desired compound (523 mg;76.1%). ¹H-NMR (DMSO-d₆): 8.32 (1H, s), 8.02 (2H, J=4.3 Hz, d), 8.00(2H, J=4.3 Hz, d), 4.68 (2H, m), 3.50 (2H, m), 3.32 (1H, m), 3.44 (3H,s), 3.05 (1H, m), 2.22 (2H, m), 1.83 (2H, J=17 Hz, d), 1.25 (6H, J=7 Hz,d) ppm. LCMS: 469.4, 384.9, 357.2.

The starting material, 4,6-Dichloro-pyrimidine-5-carbonitrile, used inthe preparation of Compound A91 was prepared in the following manner: Toa solution of 5-formyl-4,6-dichloropyrimidine (3.6 g, 20.3 mmol) inEtOAc (50 ml), was added a solution of NH₂OH.HCl (1.41 g, 20.3 mmol) inH₂O (30 ml) followed by AcONa (1.67 g, 20.3 mmol) at rt. After stirringfor 2 h, the reaction was washed with H₂O (50 ml, two times) and driedover MgSO₄. The EtOAc was concentrated under vacuum to afford the crudeiminohydroxy compound (3.51 g, 90.2%). The crude compound was used fornext step without further purification. The iminohydroxy compound (3.51g, 18.3 mmol) was dissolved in SOCl₂ (20 ml) at 0° C. and stirred for 30min. The reaction was warmed to rt and maintained for 3 h. The reactionwas poured into H₂O (100 g) portionwise and stirred for 30 min. Theprecipitate was filtered, washed with H₂O (100 mL) and dried undervacuum to afford 4,6-Dichloro-pyrimidine-5-carbonitrile (2.99 g, 91%).¹H-NMR (DMSO-d₆): 8.53 ppm; LCMS: not detectable.

Compound A921-[6-(4-Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 7]. The residue was purified by preparatory LCMS. ¹H NMR, 400MHz, CDCl₃, δ (ppm): 8.19 (s, 1H); 7.38 (d, 2H); 7.08 (d, 2H); 6.47 (m,1H); 5.43 (s, 2H); 4.12 (q, 2H); 3.93 (m, 2H); 3.12 (m, 2H); 2.56 (m,1H); 1.96 (m, 2H); 1.76 (m 2H); 1.23 (t, 31-1). LCMS (ESI) forC₂₀H₂₂F₂N₄O₆: m/z 452 (M+H⁺, 100%).

Compound A931-[6-(3-Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 7]: The residue was purified by preparatory LCMS. ¹H NMR, 400MHz, CDCl₃, δ (ppm): 8.16 (s, 1H); 7.29 (t, 1H); 7.17 (d, 1H); 7.11 (s,1H); 7.00 (d, 1H); 6.45 (m, 1H); 5.40 (s, 2H); 4.08 (q, 2H); 3.89 (m,2H); 3.08 (m, 2H); 2.52 (m, 1H); 1.92 (m, 2H); 1.74 (m 2H); 1.19 (t,3H). LCMS (ESI) for C₂₀H₂₂F₂N₄O₆: m/z 452 (M+H⁺, 100%).

Compound A942-{1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-ethanol

[methods 2 followed by 3]. Purification by HPLC yielded brownish oil.Yield 21%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.50 (s, 1H); 6.76 (s, 1H);4.37 (d, 2H); 4.04 (s, 3H); 3.99 (m, 2H); 3.33 (t, 2H); 1.82 (m, 8H).LCMS (ESI) m/z 417 (M+H⁺, 100%)

Compound A953-{1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-propionicacid

[method 2 followed by 3]. Purification by HPLC yielded brownish solid.Yield 21%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.20 (s, 1H); 6.45 (s, 1H);4.07 (d, 2H); 3.74 (s, 3H); 3.01 (m, 2H); 2.33 (m, 2H); 2.19 (m, 2H);1.58 (m, 4H); 1.28 (m, 4H). LCMS (ESI) m/z 459 (M+H⁺, 100%)

Compound A964-[4-(4-Methyl-benzyl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine

[method 2 followed by 3]. Purification by Flash Chromatography yieldedan yellow oil. Yield 29%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.25 (s, 1H);7.11 (m, 2H); 7.04 (m, 2H); 6.51 (s, 1H); 4.12 (m, 2H); 3.79 (s, 3H);3.03 (t, 2H); 2.57 (d, 2H); 2.34 (s, 3H); 1.83 (m, 3H); 1.33 (m, 2H).LCMS (ESI) m/z 477 (M+H⁺, 100%)

Compound A974-(3-Methanesulfonyl-pyrrolidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine

[methods 2 and 3]. Purification by HPLC yielded brownish oil. Yield 30%.LCMS (ESI) m/z 438 (M+H⁺, 100%)

Compound A984-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidine

[methods 2 and 3]. Purification by HPLC yielded orange solid. Yield 77%.¹H NMR 400 MHz CDCl₃ δ (ppm): 8.29 (s, 1H); 7.1 (d, 1H); 7.51 (t, 1H);7.02 (m, 2H); 6.54 (s, 1H); 3.82 (m, 7H); 2.09 (m, 5H). LCMS (ESI) m/z533.1 (M+H⁺, 100%)

Compound A994-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine

[methods 2 and 3]. Purification by HPLC yielded A99 as a brown oil.Yield 12%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.31 (s, 1H); 6.54 (s, 1H);4.22 (d, 2H); 3.82 (s, 3H); 3.12 (m, 2H); 2.40 (m, 1H); 2.03 (m, 2H);1.72 (m, 2H). LCMS (ESI) m/z 482.1 (M+H⁺, 100%)

Compound A1004′-(4-Benzoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester

[method 1a]. Purification by HPLC provided compound A100 as yellow solid(43 mg, 41%). ¹H NMR 400 MHz CDCl₃ δ(ppm): 7.84 (d, 1H); 7.81 (s, 2H);7.73 (d, 2H); 7.52 (t, 1H); 7.41 (q, 2H); 7.17 (d, 2H); 6.57 (d, 1H);4.10 (q, 2H); 3.48 (dt, 2H); 3.03 (td, 2H); 2.50 (m, 5H); 1.96 (dd, 2H);1.81 (td, 2H); 1.21 (t, 3H). Exact mass calculated for C₂₆H₂₅N₃O₆ 475.17LCMS (ESI) m/z 476.0 (M+H⁺, 100%).

Compound A1013′-Nitro-4′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester

[method 1]. Purification by HPLC provided compound A101 as yellow oil(49 mg, 49%). ¹H NMR 400 MHz CDCl₃ δ(ppm): 7.89 (d, 1H); 7.21 (d, 2H);7.05 (d, 2H); 6.60 (d, 1H); 4.19 (q, 2H); 3.56 (dt, 2H); 3.12 (td, 2H);2.91 (t, 2H); 2.78 (t, 2H); 2.59 (t, 1H); 2.17 (s, 3H); 2.04 (dd, 2H);1.89 (m, 2H); 1.30 (t, 3H). Exact mass calculated for C₂₃H₂₇N₃O₆ 441.19LCMS (ESI) m/z 442.5 (M+H⁺, 100%).

Compound A1024′-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester

[method 1a]. HPLC provided compound A102 as yellow solid (28 mg, 27%).¹H NMR 400 MHz CDCl₃ δ (ppm): 8.03 (d, 2H); 7.92 (d, 1H); 7.24 (d, 2H);6.65 (d, 1H); 4.19 (q, 2H); 3.57 (dd, 2H); 3.12 (td, 2H); 2.62 (s, 3H);2.59 (m, 1H); 2.05 (dd, 2H); 1.90 (m, 2H); 1.30 (t, 3H). Exact masscalculated for C₂₃H₂₅N₃O₈ 471.16 LCMS (ESI) m/z 472.4 (M+H⁺, 100%).

Compound A1034′-(2-Amino-4-ethanesulfonyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester

[method 1a]. HPLC provided compound A103 as brown solid (61 mg, 57%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 9.83 (s, 1H); 7.97 (d, 1H); 7.45 (dd, 1H);7.10 (d, 1H); 6.76 (d, 1H); 4.10 (q, 2H); 3.45 (d, 2H); 3.16 (m, 4H);2.69 (m, 1H); 1.93 (d, 2H); 1.69 (t, 2H); 1.18 (t, 3H); 1.12 (t, 3H).Exact mass calculated for C₂₁H₂₆N₄O₇S 478.15 LCMS (ESI) m/z 479.2 (M+H⁺,100%).

Compound A1044′-(4-Imidazol-1-yl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester

[method 1a]. HPLC provided compound A104 as brown oil (64 mg, 65%). ¹HNMR 400 MHz CDCl₃ δ (ppm): 8.85 (s, 1H); 7.90 (d, 1H); 7.57 (d, 1H);7.53 (dd, 2H); 7.45 (d, 1H); 7.41 (dd, 2H); 4.20 (q, 2H); 3.56 (d, 2H);3.13 (td, 2H); 2.60 (m, 1H); 2.06 (dd, 2H); 1.90 (td, 2H); 1.30 (t, 3H).Exact mass calculated for C₂₂H₂₃N₅O₅ 437.17 LCMS (ESI) m/z 438.3 (M+H⁺,100%).

Compound A1054-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-trifluoromethyl-piperidin-1-yl)-pyrimidine

[method 2 followed by 3]. Purification by HPLC yielded orange oil. Yield41%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.31 (s, 1H); 6.54 (s, 1H); 4.22 (d,2H); 3.82 (s, 3H); 3.12 (m, 2H); 2.40 (m, 1H); 2.03 (m, 2H); 1.72 (m,2H). LCMS (ESI) m/z 481.1 (M⁺H⁺, 100%)

Compound A1064-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidine

[method 3]. Purification by HPLC yielded A106 as an orange solid. Yield55%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.28 (s, 1H); 7.47 (m, 2H); 7.34 (m,2H); 6.53 (s, 1H); 4.03 (d, 2H); 3.82 (s, 3H); 3.42 (m, 1H); 3.33 (m,2H); 2.09 (m, 3H); 1.74 (m, 2H). LCMS (ESI) m/z 481.1 (M+H⁺, 100%)

Compound A1071-[6-(3-Ethynyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Purification by semi preparatory HPLC afforded the pureproduct in 50%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.12 (s, 1H); 7.30 (m,2H); 7.19 (s, 1H); 7.06 (m, 1H); 4.10 (q, 2H); 3.95 (m, 2H); 3.14 (m,2H); 3.03 (s, 1H); 2.56 (m, 1H); 1.95 (m, 2H); 1.76 (m, 2H); 1.20 (t,3H). LCMS (ESI) for C₂₀H₂₀N₄O₅: m/z 396 (M+H⁺, 100%).

Compound A1081-[6-(4-Chloro-2-fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. Purified by semi preparatory HPLC afforded the pure productin 42%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.00 (s, 1H); 7.06 (m, 3H);4.02 (q, 2H); 3.86 (m, 2H); 3.07 (m, 2H); 2.48 (m, 1H); 1.87 (m, 2H);1.69 (m, 2H); 1.12 (t, 3H). LCMS (ESI) for C₁₈H₁₈ClFN₄O₅: m/z 424 (M+H⁺,100%).

Compound A1091-[6-(2,4-Difluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. purified by semi preparatory HPLC afforded the pure productin 34%.

¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.14 (s, 1H); 7.15 (m, 1H); 6.89 (m,2H); 4.14 (q, 2H); 3.98 (m, 2H); 3.19 (m, 2H); 2.60 (m, 1H); 2.00 (m,2H); 1.82 (m, 2H); 1.24 (t, 3H). LCMS (ESI) for C₁₈H₁₈F₂N₄O₅: m/z 408(M+H⁺, 100%).

Compound A1101-[6-(4-Bromo-2-fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. purified by semi preparatory HPLC afforded the pure productin 41%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.07 (s, 1H); 7.26 (m, 2H);7.02 (t, 1H); 4.09 (q, 2H); 3.94 (m, 2H); 3.14 (m, 2H); 2.55 (m, 1H);1.95 (m, 2H); 1.76 (m, 2H); 1.19 (t, 3H). LCMS (ESI) for C₁₈H₁₈BrFN₄O₅:m/z 468 (M+H⁺, 100%).

Compound A1114-(3-Ethynyl-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine

[method 1a]. purified by semi preparatory HPLC afforded the pure productin 28%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.07 (s, 1H); 7.28 (m, 2H);7.19 (m, 1H); 7.05 (m, 1H); 4.00 (m, 2H); 3.01 (s, 1H); 2.93 (m, 2H);1.71 (m, 2H); 1.48 (m, 1H); 1.28 (m, 2H); 1.16 (m, 4H); 0.83 (t, 3H).LCMS (ESI) for C₂₀H₂₂N₄O₃: m/z 366 (M+H⁺, 100%).

Compound A1124-(4-Chloro-2-fluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine

[method 1a]. Purified by semi preparatory HPLC afforded the pure productin 39%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.04 (s, 1H); 7.13 (m, 3H);4.01 (m, 2H); 2.94 (m, 2H); 1.71 (m, 2H); 1.49 (m, 1H); 1.28 (m, 2H);1.16 (m, 4H); 0.82 (t, 3H). LCMS (ESI) for C₁₈H₂₀ClFN₄O₃: m/z 394 (M+H⁺,100%).

Compound A1134-(2,4-Difluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine

[method 1a]. purified by semi preparatory HPLC afforded the pure productin 54%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.04 (s, 1H); 7.10 (m, 1H);6.85 (m, 2H); 4.00 (m, 2H); 2.94 (m, 2H); 1.71 (m, 2H); 1.49 (m, 1H);1.28 (m, 2H); 1.16 (m, 4H); 0.82 (t, 3H). LCMS (ESI) for C₁₈H₂₀F₂N₄O₃:m/z 378 (M+H⁺, 100%).

Compound A1144-(4-Bromo-2-fluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine

[method 1a]. purified by semi preparatory HPLC afforded the pure productin 62%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.15 (s, 1H); 7.35 (m, 2H);7.12 (t, 1H); 4.10 (m, 2H); 3.10 (m, 2H); 1.81 (m, 2H); 1.59 (m, 1H);1.36 (m, 2H); 1.26 (m, 4H); 0.93 (t, 3H). LCMS (ESI) for C₁₈H₂₀BrFN₄O₃:m/z 438 (M+H⁺, 100%).

Compound A1153′-Nitro-2′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-4-carboxylicacid ethyl ester General Procedure 2:

Intermediate monochloro as a yellow oil (128 mg, 80% yield). Exact masscalculated for C15H₁₃ClN₂O₄ 320.06, LCMS (ESI) m/z 320.8 (M+H⁺, 100%).[method 1a]. HPLC provided compound A119 as yellow oil (44 mg, 50%). ¹HNMR 400 MHz CDCl₃ δ(ppm); 8.30 (d, 1H); 7.42 (d, 2H); 7.18 (d, 2H); 6.40(d, 1H); 4.34 (q, 2H); 3.95 (dt, 2H); 3.36 (td, 2H); 3.10 (t, 2H); 2.96(t, 2H); 2.74 (m, 1H); 2.34 (s, 3H); 2.20 (dt, 2H); 2.05 (td, 2H); 1.44(t, 3H). Exact mass calculated for C₂₃H₂₇N₃O₆ 441.19 LCMS (ESI) m/z442.3 (M+H⁺, 100%).

Compound A1164-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-yloxy)-phenyl]-butan-2-one

[method 1a]. HPLC provided compound A116 as yellow oil (34 mg, 32%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 8.09 (d, 1H); 7.24 (d, 2H); 7.00 (d, 2H); 6.15(d, 1H); 3.80 (d, 2H); 3.06 (td, 2H); 2.91 (t, 2H); 2.77 (t, 2H); 1.77(d, 2H); 1.51 (m, 1H); 1.36-1.22 (m, 6H); 0.8 (t, 3H). Exact masscalculated for C₂₃H₂₉N₃O₄ 411.22 LCMS (ESI) m/z 412.4 (M+H⁺, 100%).

Compound A1172′-(4-Benzoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylicacid ethyl ester

[method 1a]. HPLC provided compound A117 as yellow oil (37 mg, 39%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 8.24 (d, 1H); 7.97 (d, 2H); 7.86 (d, 2H); 7.68(t, 1H); 7.57 (t, 2H); 7.27 (d, 2H); 6.36 (d, 1H); 4.23 (q, 2H); 3.87(dt, 2H); 3.23 (td, 2H); 2.66-2.60 (m, 1H); 2.08 (dt, 2H); 1.92 (td,2H); 1.33 (t, 3H). Exact mass calculated for C₂₆H₂₅N₃O₆ 475.17 LCMS(ESI) m/z 476.2 (M+H⁺, 100%).

Compound A1184-(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one

[method 1a]. The crude was dissolved in dichloromethane and purified bypreparative TLC. [SiO₂; 20/80 EtOAc/hexanes]. Yield 37 mg, 48%. Yellowsolid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 8.36 (d, 1H); 8.11 (s, 1H); 7.42(ddd, 1H); 7.11 (m, 3H); 6.95 (m, 3H); 4.12 (heptet, 1H); 3.94 (tt, 2H);3.33 (m, 2H); 2.84 (m, 2H); 2.70 (m, 2H); 2.15 (m, 2H); 2.08 (s, 3H);1.75 (m, 2H). LCMS (ESI), m/z 480 (M+H⁺, 100%)

Compound A119[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-yloxy)-phenyl]-phenyl-methanone

General Procedure 2: Intermediate monochloro as a yellow oil (142 mg,80% yield). Exact mass calculated for C₁₈H₁₁ClN₂O₄ 354.04, LCMS (ESI)m/z 355.2 (M+H⁺, 100%). [method 1a]. HPLC provided compound A119 asyellow solid (26 mg, 29%). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.33 (d, 1H);8.07 (d, 2H); 7.94 (d, 2H); 7.77 (m, 1H); 7.65 (t, 2H); 7.37 (d, 2H);6.44 (d, 1H); 3.96 (d, 2H); 3.28 (td, 2H); 1.95 (d, 2H); 1.71-1.65 (m,1H); 1.51-1.38 (m, 6H); 1.1 (t, 3H). Exact mass calculated forC₂₆H₂₇N₃O₄ 445.20 LCMS (ESI) m/z 446.0 (M+H⁺, 100%).

Compound A1204-(4-{5-Nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one

[method 2 followed by method 1]. Yield 0.173 g, 83%. Yellow solid. ¹HNMR 400 MHz CDCl₃d □(ppm): 8.30 (s, 1H); 7.53 (m, 1H); 7.42 (m, 1H);6.93 (m, 2H); 4.75 (m, 1H); 3.77 (m, 2H); 3.56 (m, 2H); 1.95 (m, 4H).LCMS (ESI) m/z 403 (M+H⁺, 100%)

[method 1a]. Compound A120 purified through a silica plug [SiO₂;EtOAc/hexane; 20:80]. Yield 0.067 g, 85%. Yellow oil. ¹H NMR 400 MHzCDCl₃ δ□(ppm): 8.12 (s, 1H); 7.53 (m, 1H); 7.42 (m, 1H); 7.15 (m, 2H);6.97 (m, 4H); 3.72 (m, 2H); 3.60 (m, 2H); 2.82 (m, 2H); 2.70 (m, 3H);2.08 (m, 4H); 1.97 (m, 4H). LCMS (ESI) m/z 531 (M+H⁺, 100%)

Compound A1214-(4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one

[method 1]. Purification by HPLC. Yield 52%. Yellow solid. ¹H NMR 400MHz CDCl₃ δ (ppm): 8.11 (s, 1H); 7.17 (d, 2H); 6.98 (d, 2H); 4.06 (d,2H); 3.23 (t, 2H); 3.12 (d, 2H); 3.00 (m, 2H); 2.85 (t, 2H); 2.72 (t,2H); 2.10 (s, 3H); 1.81 (m, 4H); 1.28 (m, 2H); 0.84 (t, 6H). LCMS (ESI)m/z 453 (M+H⁺, 100%)

[method 1a]. Purification by HPLC yielded a yellow solid. Yield 62%. ¹HNMR 400 MHz CDCl₃ δ (ppm): 8.13 (s, 1H); 7.15 (d, 2H); 6.98 (d, 2H);4.02 (d, 2H); 3.22 (m, 3H); 2.83 (t, 2H); 2.70 (t, 2H); 2.33 (s, 3H);2.10 (m, 5H); 1.04 (m, 2H). LCMS (ESI) m/z 453.2 (M+H⁺, 100%)

Compound A122(4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone

Purification by HPLC yielded yellow solid. Yield 68%. ¹H NMR 400 MHzCDCl₃ δ (ppm): 8.04 (s, 1H); 7.71 (d, 2H); 7.61 (d, 2H); 7.41 (m, 1H);7.30 (m, 2H); 7.08 (m, 2H); 3.92 (d, 2H); 3.13 (m, 3H); 2.21 (s, 3H);2.02 (m, 2H); 1.83 (m, 2H). LCMS (ESI) m/z 487.1 (M+H⁺, 100%)

Compound A1231-{6-[4-(4-Fluoro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 1]. HPLC provided compound A123 as yellow solid (85 mg, 86%yield). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.13 (s, 1H); 7.79 (d, 2H); 7.76(d, 2H); 7.20 (d, 2H); 7.10 (d, 2H); 4.09 (q, 2H); 3.96 (dt, 2H); 3.15(td, 2H); 2.59-2.52 (m, 1H); 1.96 (dt, 2H); 1.77 (td, 2H); 1.19 (t, 3H).Exact mass calculated for C₂₅H₂₃FN₄O₆ 494.16, LCMS (ESI) m/z 495.1(M+H⁺, 100%).

Compound A124(4-Fluoro-phenyl)-{4-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-methanone

[method 1]. HPLC provided compound A124 as yellow solid (69 mg, 84%yield). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.10 (s, 1H); 7.78 (d, 2H); 7.76(d, 2H); 7.19 (d, 2H); 7.09 (tt, 2H); 4.03 (d, 2H); 2.96 (td, 2H); 1.73(dd, 2H); 1.51 (m, 1H); 1.37 (m, 2H); 1.21 (m, 2H); 1.15 (m, 2H); 0.83(t, 3H). Exact mass calculated for C₂₅H₂₅FN₄O₄ 464.19, LCMS (ESI) m/z465.2 (M+H⁺, 100%).

Compound A1254-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine

[method 3]. Purification by HPLC yielded yellow oil. Yield 38%. ¹H NMR400 MHz CDCl₃ δ (ppm): 8.16 (s, 1H); 6.38 (s, 1H); 3.98 (d, 2H); 3.65(s, 3H); 3.21 (m, 3H); 2.26 (s, 3H); 2.08 (m, 2H); 1.89 (m, 2H). LCMS(ESI) m/z 417 (M+H⁺, 100%)

Compound A1264-(4-Methoxymethyl-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine

[method 3]. Purification by HPLC yielded A126 as a yellow oil. Yield21%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.05 (s, 1H); 630 (s, 1H); 3.93 (d,2H); 3.59 (s, 3H); 3.15 (s, 3H); 3.07 (m, 2H); 2.89 (m, 2H); 1.69 (m,3H); 1.15 (m, 2H). LCMS (ESI) m/z 417 (M+H⁺, 100%)

Compound A1274-{4-[6-(4-Methoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one

[method 1a]. Purification by HPLC yielded A127 as a yellow solid. Yield19%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.04 (s, 1H); 7.07 (d, 2H); 6.91 (d,2H); 3.98 (d, 2H); 3.22 (s, 3H); 3.14 (d, 2H); 2.92 (m, 2H); 2.76 (m,2H); 2.64 (m, 2H); 2.02 (s, 3H); 1.74 (m, 3H); 1.20 (m, 2H). LCMS (ESI)m/z 414.45 (M+H⁺, 100%)

Compound A1284-[4-(2-Methoxy-ethyl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine

[method 2 followed by 1a]. Purification by HPLC yielded orange solid.Yield 41%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.11 (s, 1H); 6.36 (s, 1H);3.97 (d, 2H); 3.65 (s, 3H); 3.33 (m, 2H); 3.22 (s, 3H); 2.93 (m, 2H);1.69 (m, 3H); 1.43 (m, 2H); 1.16 (m, 2H). LCMS (ESI) m/z 431.1 (M+H⁺,100%)

Compound A1294-{4-[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one

[method 1a] A129 was purified by HPLC. ¹H NMR 400 MHz CDCl₃ δ (ppm):8.00 (s, 1H), 7.10 (d, 2H), 6.80 (d, 2H), 3.90 (m, 2H), 3.30 (q, 2H),3.15 (d, 2H), 2.90 (m, 2H), 2.70 (t, 2H), 2.60 (t, 2H), 2.00 (s, 3H)1.70 (m, 3H), 1.20 (m, 2H), 1.00 (t, 2H). LCMS (ESI) for C₂₂H₂₈N₄O₅: m/z429.0 (M+H⁺, 100%)

Compound A1304-(2,4-Difluoro-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine

[method 1a] A130 was purified by semi preparatory HPLC afforded the pureproduct in 73%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.67 (d, 1H); 8.10 (s,1H); 7.80 (t, 1H); 7.42 (d, 1H); 7.31 (t, 1H); 7.11 (m, 1H); 6.88 (m,2H); 4.12 (m, 1H); 3.99 (m, 2H); 3.29 (m, 2H); 2.14 (m, 2H); 1.76 (m,2H). LCMS (ESI) for C₂₀H₁₇F₂N₅O₃S: m/z 445 (M+H⁺, 100%).

Compound A131(4-Methoxy-2-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone

[method 1a] Purified by semi preparatory LCMS afforded the pure productin 38%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.55 (d, 1H); 7.98 (s, 1H);7.62 (m, 3H); 7.46 (m, 2H); 7.31 (m, 3H); 7.15 (m, 1H); 6.80 (m, 1H);6.72 (d, 1H); 4.05 (m, 1H); 3.86 (m, 2H); 3.82 (s, 3H, —OCH₃); 3.22 (m,2H); 2.09 (m, 2H); 1.70 (m, 2H). LCMS (ESI) for C₂₈H₂₅N₅O₅S: m/z 543(M+H⁺, 100%).

Compound A1324-(2,4-Difluoro-phenoxy)-6-(4-ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidine

[method 1]. crude product was purified by HPLC to afford yellow oil(35.4 mg, 27%). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.20 (s, 1H), 7.20 (m,1H), 6.80 (d, 2H), 7.00-6.90 (m, 2H), 4.10 (m, 2H), 3.50 (d, 2H), 3.10(m, 2H), 2.00 (m, 1H), 1.90 (m, 2H), 1.40 (m, 2H), 1.20 (t, 3H). LCMS(ESI) for C₁₈H₂₀FN₄O₄: m/z 395.1 (M+H⁺, 100%)

Compound A1334-{4-[6-(4-Cyclopropylmethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one

[method 2 followed by method 1a]. Purification by HPLC yielded yellowsolid. Yield 53%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 7.97 (s, 1H); 7.02 (d,2H); 6.84 (d, 2H); 3.92 (d, 2H); 3.13 (m, 2H); 3.07 (m, 2H); 2.86 (m,2H); 2.71 (m, 2H); 2.57 (m, 2H); 1.56 (s, 3H); 1.70 (m, 3H); 1.13 (m,2H); 0.85 (m, 1H); 0.34 (m, 2H); 0.01 (m, 2H). LCMS (ESI) m/z 455.2(M+H⁺, 100%)

Compound A1344-{4-[5-Nitro-6-(4-propoxymethyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2-one

[method 2 followed by 1a]. Purification by HPLC yielded yellow solid.Yield 22%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.03 (s, 1H); 7.08 (d, 2H);6.90 (d, 2H); 3.98 (d, 2H); 3.24 (t, 2H); 3.16 (d, 2H); 2.92 (m, 2H);2.76 (m, 2H); 2.63 (m, 2H); 2.01 (s, 3H); 1.74 (m, 3H); 1.45 (m, 2H);1.19 (m, 2H); 0.78 (t, 3H). LCMS (ESI) m/z 443.3 (M+H⁺, 100%)

Compound A1351-{4-[6-(4-Methoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-ethanone

[method 1a]. Yield 12%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.03 (s, 1H); 7.89(d, 2H); 7.10 (d, 2H); 3.99 (d, 2H); 3.21 (t, 3H); 3.13 (m, 2H); 2.93(m, 2H); 2.47 (s, 3H); 1.75 (m, 3H); 1.19 (m, 2H). LCMS (ESI) m/z 387(M⁺H⁺, 100%)

Compound A1364-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-butan-2-one

Following general procedure 1, compound A136 was obtained as a yellowoil (70%). ¹HNMR (CDCl₃, 400 MHz) δ 0.70 (t, 3H), 1.04-1.17 (m, 7H),1.53 (d, 2H), 1.97 (s, 3H), 2.54-2.70 (m, 6H), 3.10 (d, 2H), 6.36 (d,2H), 6.69 (d, 1H), 6.77 (d, 2H), 6.96 (d, 2H), 7.04 (t, 1H). Exact masscalculated for C₂₄H₃₀N₂O₄ 410.22, found 411.2 (MH⁺).

Compound A1371-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-ethanone

Following the general procedure 1, compound A137 was obtained as ayellow solid (11%) ¹HNMR (CDCl₃, 400 MHz) δ 0.82 (t, 3H), 1.17-1.28 (m,7H), 1.64 (d, 2H), 2.50 (s, 3H), 2.67 (t, 2H), 3.20 (d, 2H), 6.58 (d,1H), 6.89 (d, 1H), 6.98 (d, 2H), 7.24 (t, 1H), 7.88 (d, 2H). Exact masscalculated for C₂₂H₂₆N₂O₄ 382.19, found 383.3 (MH⁺).

Compound A138{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-phenyl-methanone

The intermediate monofluoro was made by method 2. It was obtained as ayellow solid (88% yield). ¹HNMR (CDCl₃, 400 MHz) δ 0.88 (t, 3H),1.24-1.33 (m, 7H), 1.71 (m, 2H), 2.74 (t, 2H), 3.23 (d, 2H), 6.77 (t,1H), 6.87 (d, 1H), 7.30 (d, 1H). Exact mass calculated for C₁₄H₁₉FN₂O₂266.14, found 297.0 (MH⁺).

Following the general procedure 2, compound A138 was obtained as ayellow oil (72%). ¹HNMR (CDCl₃, 400 MHz) δ 0.75 (t, 3H), 1.10-1.24 (m,7H), 1.59-1.62 (m, 2H), 2.67 (t, 2H), 3.20 (d, 2H), 6.59 (d, 1H), 6.88(d, 1H), 6.95 (d, 2H), 7.21 (t, 1H), 7.34 (t, 2H), 7.44 (t, 1H), 7.63(d, 2H), 7.68 (d, 2H). Exact mass calculated for C₂₇H₂₈N₂O₄ 444.20,found 445.1 (MH⁺).

Compound A1393-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-3-oxo-propionicacid methyl ester

[method 1]. Following the general procedure, compound A139 was obtainedas a yellow solid (6%). ¹HNMR (CDCl₃, 400 MHz) δ 0.71 (t, 3H), 0.99-1.16(m, 7H), 1.54 (m, 2H), 2.33-235 (m, 2H), 2.62 (m, 2H), 3.68 (s, 3H),6.74 (d, 1H), 6.96 (d, 2H), 7.06 (d, 1H), 7.37 (t, 1H), 7.83 (d, 2H).Exact mass calculated for C₂₄H₂₈N₂O₆ 440.19, found 399.2 (MH⁺).

Compound A1404-{4-[6-(4-Butoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one

[method 1a]. Purification by HPLC yielded yellow oil. Yield 41%. ¹H NMR400 MHz CDCl₃ δ (ppm): 8.03 (s, 1H); 7.08 (d, 2H); 6.89 (d, 2H); 3.97(d, 2H); 3.27 (t, 2H); 3.16 (d, 2H); 2.90 (m, 2H); 2.76 (t, 2H); 2.63(t, 2H); 2.02 (s, 3H); 1.74 (m, 1H); 1.70 (d, 2H); 1.41 (m, 2H); 1.22(m, 4H); 0.78 (t, 3H). LCMS (ESI) m/z 457 (M⁺H⁺, 100%)

Compound A1414-{4-[6-(4-Isobutoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one

[method 1a]. Purification by HPLC yielded yellow oil. Yield 45%. ¹H NMR400 MHz CDCl₃ δ (ppm): 8.11 (s, 1H); 7.17 (d, 2H); 6.98 (d, 2H); 4.06(d, 2H); 3.23 (t, 2H); 3.12 (d, 2H); 3.00 (m, 2H); 2.85 (t, 2H); 2.72(t, 2H); 2.10 (s, 3H); 1.81 (m, 4H); 1.28 (m, 2H); 0.84 (t, 6H). LCMS(ESI) m/z 457 (M⁺H⁺, 100%)

Compound A142(4-Fluoro-phenyl)-[4-(3′-nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-yloxy)-phenyl]-methanone

General Procedure 2 provided the monochloro intermediate as yellowcrystal (484 mg, 66% yield). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.21 (d, 1H);6.91 (d, 1H); 3.62 (d, 2H); 3.09 (td, 2H); 1.89 (d, 2H); 1.61 (m, 1H);1.50-1.34 (m, 6H); 1.03 (t, 3H). Exact mass calculated for C₁₃H₁₈ClN₃O₂283.11, LCMS (ESI) m/z 284.3 (M+H⁺, 100%).

[method 1a]. HPLC provided compound A142 as tan solid (34 mg, 37%yield). ¹H NMR 400 MHz CDCl₃ δ (ppm): 7.83 (d, 1H); 7.78 (d, 2H); 7.75(d, 2H); 7.15 (d, 2H); 7.11 (d, 2H); 6.58 (d, 1H); 3.51 (d, 2H); 2.97(td, 2H); 1.73 (dd, 2H); 1.49-1.42 (m, 1H); 1.31-1.17 (m, 6H); 0.84 (t,3H). Exact mass calculated for C₂₆H₂₆FN₃O₄ 463.19, LCMS (ESI) m/z 464.0(M+H⁺, 100%).

Compound A1434-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-yloxy)-phenyl]-butan-2-one

[method 1a]. HPLC provided compound A143 as yellow solid (57 mg, 70%yield). ¹H NMR 400 MHz CDCl₃ δ(ppm): 7.75 (d, 1H); 7.11 (d, 2H); 6.95(d, 2H); 6.46 (d, 2H); 3.46 (d, 2H); 2.90 (td, 2H); 2.81 (t, 2H); 2.68(t, 2H); 2.07 (s, 3H); 1.69 (m, 2H); 1.43-1.38 (m, 1H); 1.29-1.16 (m,6H); 0.83 (t, 3H). Exact mass calculated for C₂₃H₂₉N₃O₄ 411.22, LCMS(ESI) m/z 412.0 (M+H⁺, 100%).

Compound A1443′-Nitro-4-propyl-4′-(4-[1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

[method 1a]. HPLC provided compound A144 as yellow solid (46 mg, 56%yield). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.62 (s, 1H); 8.08 (s, 1H); 7.72(d, 1H); 7.58 (d, 2H); 7.18 (d, 2H); 6.49 (d, 1H); 3.43 (d, 2H); 2.89(td, 2H); 1.66 (d, 2H); 1.42-1.35 (m, 1H); 1.25-1.11 (m, 6H); 0.79 (t,3H). Exact mass calculated for C₂₁H₂₄N₆O₃ 408.19, LCMS (ESI) m/z 409.0(M+H⁺, 100%).

Compound A1451-{2-Nitro-3-[4-(3-oxo-butyl)-phenoxy]-phenyl}-piperidine-4-carboxylicacid ethyl ester

The intermediate monofluoro was made by method 2. It was obtained as ayellow solid (90% yield). ¹HNMR (CDCl₃, 400 MHz) δ 1.20 (t, 3H),1.77-1.93 (m, 4H), 2.35 (m, 1H), 2.73-2.79 (t, 2H), 3.18-3.22 (m, 2H),4.08 (q, 2H), 6.77-6.86 (m, 2H), 7.25-7.31 (m, 1H). Exact masscalculated for C₁₄H₁₇FN₂O₄ 296.12, found 297.2. Following generalprocedure 1, compound A145 was obtained as a yellow oil (61%). ¹HNMR(CDCl₃, 400 MHz) δ 1.19 (t, 3H), 1.77-1.83 (m, 2H), 1.88-1.92 (m, 2H),2.07 (s, 3H), 2.30-2.33 (m, 1H), 2.66-2.82 (m, 6H), 3.18-3.22 (m, 2H),4.07 (q, 2H), 6.50 (d, 1H), 6.79 (d, 1H), 6.88 (d, 2H), 7.08 (d, 2H),7.16 (t, 1H). Exact mass calculated for C₂₄H₂₈N₂O₆ 440.19, found 441.1(MH⁺).

Compound A1461-[3-(4-Benzoyl-phenoxy)-2-nitro-phenyl]-piperidine-4-carboxylic acidethyl ester

-   [method 2]. Intermediate was obtained as a yellow solid (90% yield).    ¹HNMR (CDCl₃, 400 MHz) δ 1.20 (t, 3H), 1.77-1.93 (m, 4H), 2.35 (m,    1H), 2.73-2.79 (t, 2H), 3.18-3.22 (m, 2H), 4.08 (q, 2H), 6.77-6.86    (m, 2H), 7.25-7.31 (m, 1H). Exact mass calculated for C₁₄H₁₇FN₂O₄    296.12, found 297.2 (MH⁺). Following the general procedure 1,    compound A146 was obtained as a yellow solid (44%). ¹HNMR (CDCl₃,    400 MHz) δ 1.20 (t, 3H), 1.80-1.91 (m, 4H), 2.37 (m, 1H), 2.74-2.81    (m, 2H), 3.22-3.25 (m, 2H), 4.10 (q, 2H), 6.68 (d, 1H), 6.93 (d,    1H), 7.02 (d, 2H), 7.29 (t, 1H), 7.42 (t, 1H), 7.52 (d, 1H), 7.70    (d, 2H), 7.76 (d, 2H). Exact mass calculated for C₂₇H₂₆N₂O₆ 474.18,    found 475.2 (MH⁺).

Compound A147{4-[6-(4-Ethoxy-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-(4-fluoro-phenyl)-methanone

[method 1a]. Purification by HPLC. Yield 24%. ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.03 (s, 1H); 7.66 (m, 4H); 7.07 (m, 2H); 6.98 (m, 2H); 3.65 (m,2H); 3.48 (m, 1H); 3.39 (q, 2H); 3.25 (m, 2H); 1.77 (m, 2H); 1.56 (m,2H); 1.06 (t, 3H). LCMS (ESI) m/z 467 (M⁺H⁺, 100%)

Compound A1481-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-ol

[method 3]. Purification by HPLC. Yield 35% yellow oil. ¹H NMR 400 MHzDMSO δ (ppm): 8.26 (s, 1H); 6.67 (s, 1H); 4.82 (s, 1H); 3.75 (m, 2H);3.68 (s, 3H); 3.31 (m, 2H); 1.76 (m, 2H); 1.41 (m, 2H). LCMS (ESI) m/z389 (M⁺H⁺, 100%)

Compound A1491-[6-(4-Acetyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. The mixture was purified by HPLC to give compound A149 as ayellow solid (57 mg, 70%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.80-1.90 (m, 2H), 1.98-2.03 (m, 2H), 2.62 (s, 3H), 3.22 (t, 2H),3.97-4.03 (m, 2H), 4.17 (q, 2H), 7.25 (d, 2H), 8.02 (d, 2H), 8.17 (s,1H). Exact mass calculated for C₂₀H₂₂N₄O₆ 414.15, found 415.2 (MH⁺).

Compound A150(1-{6-[4-(4-Fluoro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidin-4-yl)-(4-fluoro-phenyl)-methanone

[method 1a]. Purification by HPLC. Yield 40% of a yellow solid as TFAsalt. ¹H NMR 400 MHz CDCl₃ δ (ppm): 10.0 (s, 1H); 8.19 (s, 1H); 8.01 (m,2H); 7.91 (m, 2H); 7.76 (m, 4H); 7.19 (m, 2H); 7.09 (m, 4H); 4.06 (d,2H); 3.52 (m, 1H); 3.25 (m, 2H); 1.88 (m, 4H). LCMS (ESI) m/z 545.4(M⁺H⁺, 100%)

Compound A1514-(4-{6-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one

[method 1a]. Purification by HPLC yielded yellow solid. Yield 62%. ¹HNMR 400 MHz CDCl₃ δ (ppm): 8.25 (s, 1H); 8.04 (m, 2H); 7.26 (m, 4H);7.10 (d, 2H); 4.19 (m, 2H); 3.61 (m, 1H); 3.35 (m, 2H); 2.96 (t; 2H);2.83 (t, 2H); 2.21 (s, 3H); 2.00 (m, 4H). LCMS (ESI) m/z 493.4 (M⁺H⁺,100%)

Compound A1524-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-cyclohexyl]-pyrimidine

[method 1a]. The crude was dissolved in DMF and purified by HPLC. Yellowsolid. Yield 66 mg, 72%. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 8.43 (m, 1H);8.12 (s, 1H); 7.94 (tt, 2H); 7.49 (ddd, 1H); 7.28 (tt, 2H), 7.15 (m,1H); 7.01 (m, 1H); 4.10 (heptet, 1H); 3.96 (m, 2H); 3.34 (m, 2H); 3.00(s, 3H); 2.15 (m, 2H); 1.75 (m, 2H). LCMS (ESI), m/z 488 (M+H+, 100%)

Compound A1534-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-4-ylsulfanyl)-cyclohexyl]-pyrimidine

[method 1a]. The crude was dissolved in dichloromethane and purified byHPLC. Yellow solid. Yield 85 mg, 87%. ¹H-NMR (400 MHz, CDCl₃) δ(ppm):8.41 (m, 2H); 8.10 (s, 1H); 7.94 (m, 2H); 7.79 (m, 2H); 7.33 (m, 2H);4.02 (m, 3H); 3.37 (m, 2H); 3.06 (s, 3H); 2.20 (m, 2H); 1.78 (m, 2H).LCMS (ESI), m/z 488 (M+H⁺, 100%)

Compound A1544-(4-Methanesulfonyl-phenoxy)-5-nitro-6-(4-phenylsulfanyl-cyclohexyl)-pyrimidine

[method 1a]. The crude was dissolved in dichloromethane and purified byHPLC. Yellow solid. Yield 80 mg, 83%. ¹H-NMR (400 MHz, CDCl₃) δ(ppm):7.97 (s, 1H); 7.78 (m, 2H); 7.21 (m, 2H); 7.15 (m, 3H); 7.08 (m, 2H);3.80 (m, 2H); 3.16 (heptet, 1H); 3.06 (m, 2H); 2.86 (s, 3H); 1.87 (m,2H); 1.50 (m, 2H). LCMS (ESI), m/z 487 (M+H⁺, 100%)

Compound A1551-[5-Nitro-6-(4-trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 1a]. yellow solid (92%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H),1.79 (m, 2H), 1.98 (m, 2H), 2.58 (m, 1H), 3.18 (t, 2H), 3.85 (m, 2H),4.10 (q, 2H), 7.58 (d, 2H), 7.67 (d, 1H), 8.09 (s, 1H), 10.13 (s, 1H).Exact mass calculated for C₁₉H₂₀F₃N₅O₄S 471.45, found 472.1 (MH⁺).

Compound A1565-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine

Using the method described herein Compound A156 was prepared. The crudemixture was purified by flash chromatography, eluted with 50% ethylacetate/hexane to afford Compound A156 (316.5 mg, 67.8%). ¹H NMR 400 MHzCDCl₃ δ (ppm): 8.24 (s, 1H), 7.93 (d, 2H), 7.26 (d, 2H), 5.95 (s, 1H),4.10 (m, 2H), 3.96 (m, 2H), 3.17 (q, 1H), 3.02 (s, 3H), 2.14 (m, 2H),1.95 (m, 2H), 1.28 (d, 6H). LCMS (ESI) for C₂₄H₂₉N₅O₆S: m/z 516.3 (M+H⁺,100%)

Compound A1574-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine-5-carbaldehyde

Compound A156 was hydrolyzed using HCl aq in a mixture ofacetone/acetonitrile to give Compound A157 (30.0 mg, 93.72%); ¹H NMR 400MHz CDCl₃ δ (ppm): 10.3 (s, 1H), 8.17 (s, 1H), 7.96 (d, 2H), 7.32 (d,2H), 4.12 (m, 2H), 3.30 (m, 2H), 3.22 (m, 1H), 3.00 (s, 3H), 3.00 (q,1H), 2.06 (m, 2H), 2.00 (m, 2H), 1.27 (d, 6H). LCMS (ESI) forC₂₂H₂₅N₅O₅S: m/z 472.2 (M+H⁺, 100%).

Compound A1585-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine

White solid, ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.62 (s, 1H), 8.31 (s, 1H),8.08 (d, 2H), 7.28 (d, 2H), 6.06 (s, 1H), 4.24 (m, 2H), 4.13 (m, 2H),4.04 (m, 2H), 3.23 (m, 2H), 3.07 (q, 1H), 2.20 (m, 2H), 2.02 (m, 2H),1.33 (d, 6H); LCMS (ESI) for C₂₅H₂₇N₇O₄S: m/z 522.3 (M+H⁺, 100%).

The intermediate4-chloro-5-[1,3]dioxolan-2-yl-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidinewas prepared using the following method: Phosphorus Oxychloride (200 mL,2184.8 mmol) was added drop wise (additional funnel) in DMF at 0° C.,and stirred for 1 hour; treated with 4,6 dihydroxypyridimidine (50.0 g,446.1 mmol) and stirred for half hour at room temperature. Theheterogeneous mixture was refluxed for 3 hours. The volatiles wereremoved at reduce pressure, and the residue was poured in ice water andextract with chloroform and diethylether, wash with sodium bicarbonateand concentrate under high vacuum. The resulting mixture was purified onsilica (CH₂Cl₂) to afford 4,6-dichloro-pyrimidine-5-carbaldehyde as ayellow solid (54.0 g). ¹H NMR 400 MHz CDCl₃ δ (ppm): 10.3 (s, 1H,aldehyde), 8.7 (s, 1H, pyrimidine).

Compound 4,6-Dichloro-pyrimidine-5-carbaldehyde (8.6 g, 0.049 mmol),anhydrous ethylene glycol (8.2 ml) and p-Toluene-sulfonic acid (150 mg)were mixture in benzene (200 mL) and heated under reflux for 3 hours.Concentrate under high vacuum, worked up with chloroform, water, sodiumbicarbonate and sodium chloride, concentrate. The reaction mixture waspurified on silica (CH₂Cl₂) to give4,6-Dichloro-5-[1,3]dioxolan-2-yl-pyrimidine (8.86 g, 82.5%). ¹H NMR 400MHz CDCl₃ δ (ppm): 8.8 (s, 1H), 6.3 (s, 1H), 4.3 (m, 2H, 4.1 (m, 2H).

To a mixture of 4,6-dichloro-5-[1,3]dioxolan-2-yl-pyrimidine (100.0 mg,0.45 mmol) and added Potassium Carbonate (80.62 mg, 0.45 mmol) in DMF (5mL) cooled to 0° C. was added a solution of4-[1,2,3]-thiadiazol-4-yl-phenol (DMF) drop wise. The resulting mixturewas stirred at room temperature for 30 minutes to give4-chloro-5-[1,3]dioxolan-2-yl-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine.LCMS (ESI) for C₁₅H₁₁ClN₄O₃S: m/z 362.9 (M+H⁺, 100%).

Compound A1594-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carbaldehyde

White solid (18.01 mg, 25.9%); ¹H NMR 400 MHz CDCl₃ δ (ppm): 10.7 (s,1H), 8.67 (s, 1H), 8.26 (s, 1H), 8.14 (d, 2H), 7.34 (d, 2H), 4.19 (m,2H), 3.40 (m, 2H), 3.26 (m, 1H), 3.07 (q, 1H), 2.20 (m, 2H), 2.02 (m,2H), 1.33 (d, 6H). LCMS (ESI) for C₂₃H₂₃N₇O₃S: m/z 478.2 (M+H⁺, 100%).

Compound A1604-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carboxylicacid

White solid (3.8 mg, 13.63%); ¹H NMR 400 MHz MeOD δ (ppm): 9.23 (s, 1H),8.13 (d, 2H) 8.06 (s, 1H), 7.29 (d, 2H), 4.61 (m, 2H), 3.30 (m, 2H),3.05 (q, 1H), 2.15 (m, 2H), 1.97 (m, 2H), 1.32 (d, 6H); LCMS (ESI) forC₂₃H₂₃N₇O₄S: m/z 494.3 (M+H⁺, 100%).

Compound A161[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-yl]-methanol

Yellow solid (17.5 mg, 85.03%); ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.63 (s,1H), 8.31 (s, 1H), 8.11 (d, 2H), 7.27 (d, 2H), 4.77 (s, 2H), 4.23 (m,2H), 3.28 (m, 2H), 3.28 (m, 1H), 3.07 (q, 1H), 2.21 (m, 2H), 2.03 (m,2H), 1.34 (d, 6H); LCMS (ESI) for C₂₃H₂₅N₇O₃S: m/z 480.3 (M+H⁺, 100%)

Compound A162[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-ylmethyl]-dimethyl-amine

White solid, (4.2 mg, 15.83%), LCMS (ESI) for C₂₅H₃₀N₈O₂S: m/z 507.3(M+H⁺, 100%).

Compound A1634-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl-pyridin-3-yloxy)-5-nitro-pyrimidine

Compound A163 was prepared using the general procedure for the additionof amine to pyrimidine; yellow solid (82 mg, 81%). ¹H NMR 400 MHz CDCl₃δ(ppm): 8.60 (s, 1H); 8.19 (s, 1H); 8.18 (d, 1H); 7.79 (d, 1H); 4.12(db, 2H); 3.39-3.29 (m, 3H); 3.26 (s, 3H); 2.22 (db, 2H); 2.06-2.02 (m,2H); 1.36 (s, 9H). Exact mass calculated for C₂₁H₂₅N₇O₆S 503.16, LCMS(ESI) m/z 504.2 (M+H⁺, 100%).

Compound A1644-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-2-methyl-pyrimidine-5-carbonitrile

To a solution of4-chloro-6-(4-methanesulfonyl-phenoxy)-2-methyl-pyrimidine-5-carbonitrile(80.0 mg, 0.25 mmol) and4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (107.1 mg, 0.50 mmol)in DMF (1 mL) was added potassium carbonate (68.3 mg, 0.50 mmol) and theresulting mixture was left stirring for 2 hours at room temperature.Worked up with ethyl acetate, sodium bicarbonate, dried with magnesiumsulfate and evaporated. The crude product was crystallized with ethylacetate/hexane over night and filtered off to afford Compound A164 as ayellow solid (30.6 mg). LCMS (ESI) for C₂₃H₂₆N₆O₄S: m/z 483.3 (M+H⁺,100%), ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.00 (d, 2H), 7.38 (d, 2H), 4.82(m, 2H), 3.45 (m, 2H), 3.31 (m, 1H), 3.10 (s, 3H), 3.08 (m, 1H), 2.35(s, 3H), 2.24 (m, 2H), 2.03 (m, 2H), 1.34 (d, 6H).

Compound A1651-[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidin-5-yl]-ethanone

To a solution of1-[4-chloro-6-(4-methanesulfonyl-phenoxy)-pyrimidin-5-yl]-ethanone (0.21mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (0.21mmol, 49 mg) in N,N-dimethyl formamide (500 uL) was added potassiumcarbonate (0.21 mmol, 29 mg). The mixture was microwaved at 100° C. for150 seconds. Its progress was monitored by thin layer chromatography andLCMS. The reaction was treated with water and the desired compound wasextracted in ethyl acetate. Organic layer was evaporated in vacuo.Purification by HPLC provided Compound A165 as a white solid (20 mg,20%). ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 8.24 (s, 1H); 8.01 (d, 2H); 7.32(d, 2H); 4.02 (m, 2H); 3.22 (m, 3H); 3.10 (m, 1H); 3.08 (s, 3H); 2.69(s, 3H), 2.18 (m, 2H), 2.02 (m, 2H); 1.35 (d, 6H). LCMS m/z 486.3 (M+H+,100%).

Example 13 Syntheses of Compounds of the Present Invention Compound B11-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester; General Method 14

Starting material,{6-chloro-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethylester was prepared by general method 2. A mixture of6-chloro-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethylester (63 mg, 0.2 mmol), amine (1.1 eqv, 33 mg, 0.22 mmol) and potassiumcarbonate (1.1 eqv, 31 mg, 0.22 mmol) in DMF (1 ml) was stirred at 100°C. for 3 minutes in Smith microwave Synthesiser. HPLC purificationafforded compound B1 as yellow oil (59 mg, 54%). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.58 (s, 1H); 8.01 (s, 1H); 6.63 (d, 2H); 6.61 (s, 1H); 5.79 (s,2H); 4.51 (d, 2H); 3.99 (q, 2H) 3.70 (dt, 2H); 3.10 (td, 2H); 2.48 (m,1H); 1.88 (dt, 2H); 1.70 (td, 2H); 1.09 (t, 3H). Exact mass calculatedfor C₂₀H₂₃N₅O₆ 429.16, LCMS (ESI) m/z 430.0 (M+H⁺, 100%).

Compound 1321-[5-Nitro-6-(3,4,5-trimethoxy-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 14]. Filtered the reaction mixture and the filtrate was purifiedby semi preparatory HPLC afforded the pure product in 28% yield. ¹H NMR,400 MHz, CDCl₃, δ (ppm): 8.71 (m, 1H); 8.07 (s, 1H); 7.10 (s, 2H); 6.42(s, 2H); 4.56 (d, 2H); 4.02 (q, 2H); 3.71 (s, 6H); 3.69 (s, 3H); 3.16(m, 2H); 2.52 (m, 1H); 1.91 (m, 2H); 1.74 (m, 2H); 1.12 (t, 3H). LCMS(ESI) for C₂₂H₂₉N₅O₇: m/z 475 (M+H⁺, 100%).

Compound B3(5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)-(3-trifluoromethyl-benzyl)-amine

[method 14]. The product was purified by Preparatory TLC usinghexane/ethyl acetate (9:1). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.65 (s); 8.05(s, 1H, pyrimidine); 7.65 (d, 1H); 7.50 (m, 2H); 7.40 (d, 1H); 5.00 (s,2H); 3.50 (m, 4H), 1.80 (s, NH); 1.75-1.60 (m, 5H)

Compound B41-[5-Nitro-6-(2-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 14]. The residue was filtered through a silica plug [SiO₂;EtOAc/hexane; 50:50] and solvent removed in vacuo. Yield 0.143 g, 50%.Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 8.63 (m, 1H); 8.07 (s, 1H);7.68 (m, 1H); 7.53 (m, 2H); 7.40 (m, 1H); 5.01 (m, 2H); 4.17 (m, 2H);3.89 (m, 2H); 3.21 (m, 2H); 2.63 (m, 1H); 2.03 (m, 2H); 1.85 (m, 2H);1.28 (m, 3H). LCMS (ESI) m/z 390 (M+H⁺, 100%)

Compound B51-[5-Nitro-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 14]. Solvent was removed in vacuo and residue was purified bypreparatory TLC. [SiO₂; EtOAc/hexane; 10:90]. Yield 0.227 g, 73%. Yellowoil. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.69 (m, 1H); 8.06 (s, 1H); 7.60 (d,2H); 7.45 (d, 2H); 4.87 (m, 2H); 4.17 (m, 2H); 3.90 (m, 2H); 3.22 (m,2H); 2.64 (m, 1H); 2.03 (m, 2H); 1.85 (m, 2H); 1.28 (m, 3H)

Compound B61-[5-Nitro-6-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 14]. Solvent was removed in vacuo and residue was purified bypreparatory TLC. [SiO₂; EtOAc/hexane; 10:90. Yield 0.177 g, 65%. Yellowsolid. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 8.69 (m, 1H); 8.06 (s, 1H); 7.61(m, 1H); 7.54 (m, 2H); 7.48 (m, 1H); 4.87 (m, 2H); 4.17 (m, 2H); 3.90(m, 2H); 3.22 (m, 2H); 2.64 (m, 1H); 2.03 (m, 2H); 1.85 (m, 2H); 1.28(m, 3H)

Compound B7(5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)-(2-trifluoromethyl-benzyl)-amine

[method 14]. The product was purified by Preparatory TLC usinghexane/ethyl acetate (9:1). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.65 (s); 8.05(s, 1H, pyrimidine); 7.65 (d, 1H); 7.50 (m, 2H); 7.40 (d, 1H); 5.00 (s,2H); 3.50 (m, 4H), 1.80 (s, NH), 1.75-1.60 (m, 5H)

Compound B8(5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)-(4-trifluoromethyl-benzyl)-amine

The product was purified by Preparatory TLC using hexane/ethylacetate/dichloromethane (8:1:1). ¹H NMR 400 MHz CDCl₃ δ (ppm): 9.05 (s);8.05 (s, 1H, pyrimidine); 7.70 (d, 2H); 7.50 (d, 2H); 4.90 (s, 2H); 3.40(m, 4H), 1.75-1.60 (.m, 6H).

Compound B91-[5-Amino-6-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester; General Method 15

Di-substituted-5-nitropyrimidine (180 mg, 0.4 mmol) was dissolved inethyl acetate (5 mL) and flushed with N₂ gas. Palladium catalyst [5%,Pd/C] was added and hydrogen gas was introduced into the mixture. Thereaction mixture was stirred for 4 hours at room temperature. Thereaction mixture was filtered through Celite and the solvent was removedunder vacuo. Yield 0.158 g, 94%. White solid. ¹H NMR 400 MHz CDCl₃δ□(ppm): 8.69 (m, 1H); 8.06 (s, 1H); 7.61 (m, 1H); 7.54 (m, 2H); 7.48(m, 1H); 4.87 (m, 2H); 4.17 (m, 2H); 3.90 (m, 2H); 3.22 (m, 2H); 2.64(m, 1H); 2.03 (m, 2H); 1.85 (m, 2H); 1.28 (m, 3H). LCMS (ESI) m/z 424(M+H⁺, 100%)

Compound B101-[5-Amino-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 15]. Yield 0.121 g, 72%. White solid. ¹H NMR 400 MHz CDCl₃δ□(ppm): 8.13 (s, 1H); 7.58 (d, 2H); 7.46 (d, 2H); 4.75 (m, 2H); 4.17(m, 2H); 3.43 (m, 2H); 2.86 (m, 2H); 2.49 (m, 1H); 2.05 (m, 2H); 1.86(m, 2H); 1.29 (m, 3H). LCMS (ESI) m/z 424 (M+H⁺, 100%)

Compound B111-[6-(4-Bromo-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester; General Method 16

[6-chloro-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethylester (415 mg, 1.32 mmol) and 4-bromoaniline (309 mg, 1.80 mmol) weredissolved in anhydrous 1,4-dioxane (0.5-1 ml) and irradiated in a sealedmicrowave reaction tube at 250° C. for 300 seconds. The reaction mixturewas passed through a silica plug [SiO₂; EtOAc/hexane; 20:80]. Yield0.070 g, 12%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 9.98 (s, 1H);8.03 (s, 1H); 7.41 (m, 2H); 7.17 (m, 2H); 4.09 (m, 2H); 3.83 (m, 2H);3.16 (m, 2H); 2.77 (m, 1H); 1.97 (m, 2H); 1.78 (m, 2H); 1.20 (m, 3H).LCMS (ESI) m/z 451, 452 (M+H⁺, 100%)

Compound B121-[5-Nitro-6-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Yield 0.010 g, 14%. Yellow solid. ¹H NMR 400 MHz CDCl₃δ□(ppm): 10.11 (s, 1H); 8.07 (s, 1H); 7.69 (d, 2H); 7.54 (d, 2H); 4.09(m, 2H); 3.84 (m, 2H); 3.17 (m, 2H); 2.58 (m, 1H); 1.97 (m, 2H); 1.79(m, 2H); 1.20 (m, 31-1). LCMS (ESI) m/z 440 (M+H⁺, 100%)

Compound B131-[6-(Methyl-phenyl-amino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 16] Yield 0.062 g, 93%. Yellow solid. ¹H NMR 400 MHz CDCl₃δ□(ppm): 8.09 (s, 1H); 7.33 (m, 2H); 7.17 (m, 3H); 4.14 (m, 2H); 3.92(m, 2H); 3.54 (s, 3H); 3.19 (m, 2H); 2.58 (m, 1H); 1.99 (m, 2H); 1.83(m, 2H); 1.26 (m, 3H). LCMS (ESI) m/z 386 (M+H⁺, 100%)

Compound B141-[5-Nitro-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Yield 0.066 g, 92%. Yellow solid. ¹H NMR 400 MHz CDCl₃δ□(ppm): 10.09 (s, 1H); 8.11 (s, 1H); 7.63 (d, 2H); 7.22 (d, 2H); 4.17(m, 2H); 3.91 (m, 2H); 3.25 (m, 2H); 2.66 (m, 1H); 2.05 (m, 2H); 1.86(m, 2H); 1.28 (m, 3H). LCMS (ESI) m/z 456 (M+H⁺, 100%)

Compound B151-[6-(4-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Yield 0.071 g, 100%. Yellow solid. ¹H NMR 400 MHz CDCl₃δ□(ppm): 10.01 (s, 1H); 8.08 (s, 1H); 7.50 (m, 2H); 7.06 (m, 2H); 4.16(m, 2H); 3.90 (m, 2H); 3.23 (m, 2H); 2.65 (m, 1H); 2.03 (m, 2H); 1.86(m, 2H); 1.27 (m, 3H). LCMS (ESI) m/z 390 (M+H⁺, 100%)

Compound B161-[6-(3,5-Difluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Yield 0.066 g, 89%. Yellow solid. ¹H NMR 400 MHz CDCl₃δ□(ppm): 10.13 (s, 1H); 8.15 (s, 1H); 7.29 (m, 2H); 6.60 (m, 1H); 4.16(m, 2H); 3.90 (m, 2H); 3.22 (m, 2H); 2.64 (m, 1H); 2.03 (m, 2H); 1.84(m, 2H); 1.27 (m, 3H). LCMS (ESI) m/z 408 (M+H⁺, 100%)

Compound B171-[6-(3,5-Dichloro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Yield 0.023 g, 33%. Yellow solid. ¹H NMR 400 MHz CDCl₃δ□(ppm): 10.08 (s, 1H); 8.16 (s, 1H); 7.62 (m, 2H); 7.15 (m, 1H); 4.17(m, 2H); 3.91 (m, 2H); 3.23 (m, 2H); 2.66 (m, 1H); 2.05 (m, 2H); 1.85(m, 2H); 1.28 (m, 3H). LCMS (ESI) m/z 440 (M+H⁺, 100%)

Compound B181-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO2; EtOAc/hexane; 20:80]. Yield 0.063 g, 70%.Orange oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 9.96 (s, 1H); 8.09 (s, 1H);7.17 (s, 1H); 6.81 (m, 2H); 5.98 (s, 2H); 4.16 (q, 2H); 3.91 (m, 2H);3.24 (m, 2H); 2.64 (m, 1H); 2.04 (m, 2H); 1.86 (m, 2H); 1.27 (m, 3H).LCMS (ESI) m/z 416 (M+H⁺, 100%)

Compound B191-[6-(2-Bromo-4-trifluoromethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The reaction mixture was passed through a silica plug[SiO2; EtOAc/hexane; 10:90]. Yield 0.020 g, 24%. Yellow solid. ¹H NMR400 MHz CDCl₃ δ□(ppm): 10.21 (s, 1H); 8.28 (m, 1H); 8.06 (s, 1H); 7.42(m, 1H); 7.17 (m, 1H); 4.09 (m, 2H); 3.85 (m, 3.85); 3.18 (m, 2H); 2.55(m, 1H); 1.98 (m, 2H); 1.79 (m, 2H); 1.20 (m, 3H). LCMS (ESI) m/z 535,536 (M+H⁺, 100%)

Compound B201-[6-(2-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue waspurified by preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.016 g,22%. Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 10.11 (s, 1H); 8.16 (m,2H); 7.15 (m, 3H); 4.16 (m, 2H); 3.92 (m, 2H); 3.25 (m, 2H); 2.65 (m,1H); 2.03 (m, 2H); 1.86 (m, 2H); 1.28 (m, 3H). LCMS (ESI) m/z 390 (M+H⁺,100%)

Compound B211-[6-(3-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The reaction mixture was passed through a silica plug[SiO2; EtOAc/hexane; 20:80]. Yield 0.034 g, 43%. Yellow solid. ¹H NMR400 MHz CDCl₃ δ□(ppm): 10.12 (s, 1H); 8.14 (s, 1H); 7.63 (m, 1H); 7.31(m, 1H); 7.23 (m, 1H); 6.87 (m, 1H); 4.17 (m, 2H); 3.91 (m, 2H); 3.24(m, 2H); 2.65 (m, 1H); 2.05 (m, 2H); 1.86 (m, 2H); 1.28 (m, 3H). LCMS(ESI) m/z 390 (M+H⁺, 100%)

Compound B221-{6-[(2-Fluoro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. purified by preparatory TLC [SiO2; EtOAc/hexane; 20:80].Yield 0.018 g, 23%. Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 8.09 (s,1H); 7.14 (m, 2H); 7.03 (m, 2H); 4.15 (m, 2H); 3.93 (m, 2H); 3.51 (s,3H); 3.20 (m, 2H); 2.60 (m, 1H); 2.00 (m, 2H); 1.83 (m, 2H); 1.27 (m,3H). LCMS (ESI) m/z 404 (M+H⁺, 100%)

Compound B231-[6-(Ethyl-phenyl-amino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.008 g, 8%.Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 8.13 (s, 1H); 7.32 (m, 2H);7.20 (m, 2H); 7.12 (m, 1H); 4.14 (m, 4H); 3.86 (m, 2H); 3.14 (m, 5H);2.57 (m, 1H); 1.98 (m, 2H); 1.83 (m, 2H); 1.24 (m, 4H). LCMS (ESI) m/z400 (M+H⁺, 100%)

Compound B241-{6-[(4-Chloro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.008 g, 8%.Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 8.10 (s, 1H); 7.29 (d, 2H);7.10 (d, 2H); 4.15 (m, 2H); 3.93 (m, 2H); 3.52 (s, 3H); 3.21 (m, 2H);2.56 (m, 1H); 2.01 (m, 2H); 1.85 (m, 2H); 1.26 (m, 3H). LCMS (ESI) m/z420 (M+H⁺, 100%)

Compound B251-[6-(4-Difluoromethyl-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 14]. HPLC provided compound B25 as yellow oil (58 mg, 64%). ¹HNMR 400 MHz CDCl₃ δ (ppm): 8.48 (s, 1H); 8.13 (s, 1H); 7.27 (d, 2H);7.05 (d, 2H); 4.72 (d, 2H); 4.10 (q, 2H); 3.80 (dt, 2H); 3.25 (td, 2H);2.60 (m, 1H); 2.00 (dt, 2H); 1.84 (td, 2H); 1.19 (t, 3H). Exact masscalculated for C₂₀H₂₃F₂N₅O₅ 451.17, LCMS (ESI) m/z 452.1 (M+H⁺, 100%).

Compound B261-{6-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

-   [method 14]. HPLC provided compound B26 as yellow solid (62 mg,    56%). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.86 (s, 1H); 8.28 (s, 1H); 6.95    (d, 1H); 6.93 (s, 1H); 6.89 (d, 1H); 4.75 (d, 2H); 4.25 (q, 2H);    3.96 (dt, 4H); 3.87 (dt, 2H); 3.38 (td, 2H); 2.75 (m, 1H); 2.15 (dt,    2H); 1.98 (td, 2H); 1.35 (t, 3H). Exact mass calculated for    C₂₁H₂₅N₅O₆ 443.18, LCMS (ESI) m/z 444.6 (M+H⁺, 100%).

Compound B271-{6-[(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 14]. HPLC provided compound B27 as yellow solid (62 mg, 56%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 8.86 (s, 1H); 8.28 (s, 1H); 6.95 (d, 1H); 6.93(s, 1H); 6.89 (d, 1H); 4.75 (d, 2H); 4.25 (q, 2H); 3.96 (dt, 4H); 3.87(dt, 2H); 3.38 (td, 2H); 2.75 (m, 1H); 2.15 (dt, 2H); 1.98 (td, 2H);1.35 (t, 3H). Exact mass calculated for C₂₁H₂₅N₅O₆ 443.18, LCMS (ESI)m/z 444.6 (M+H⁺, 100%).

Compound B281-{6-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 14]. HPLC provided compound B28 as yellow solid (62 mg, 57%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 8.47 (s, 1H); 8.02 (s, 1H); 7.12 (s, 1H); 7.02(d, 1H); 6.68 (d, 1H); 4.62 (d, 2H); 4.50 (t, 2H); 4.09 (q, 2H); 3.81(dt, 2H); 3.15 (d, 2H); 3.12 (t, 2H); 2.55 (m, 1H); 1.95 (dt, 2H); 1.77(td, 2H); 1.19 (t, 3H). Exact mass calculated for C₂₁H₂₅N₅O₅ 427.19,LCMS (ESI) m/z 428.1 (M+H⁺, 100%).

Compound B291-{6-[(6-Fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 14]. HPLC provided compound B29 as yellow solid (77 mg, 67%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 8.92 (s, 1H); 8.09 (s, 1H); 6.88 (dd, 1H);6.58 (dd, 1H); 5.22 (s, 2H); 4.80 (s, 2H); 4.68 (d, 2H); 4.09 (q, 2H);3.80 (d, 2H); 3.19 (td, 2H); 2.57 (m, 1H); 1.96 (dt, 2H); 1.79 (td, 2H);1.19 (t, 3H). Exact mass calculated for C₂₁H₂₄FN₅O₆ 461.17, LCMS (ESI)m/z 462.3 (M+H⁺, 100%).

Compound B301-[6-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.069 g, 71%.Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 9.96 (s, 1H); 8.09 (s, 1H);7.24 (m, 1H); 7.04 (m, 1H); 6.95 (m, 1H); 4.22 (m, 6H); 3.90 (m, 2H);3.22 (m, 2H); 2.63 (m, 1H); 2.19 (m, 2H); 2.03 (m, 2H); 1.85 (m, 2H);1.26 (m, 3H). LCMS (ESI) m/z 444 (M+H⁺, 100%)

Compound B311-{6-[4-(Morpholine-4-sulfonyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.030 g, 29%.Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 10.29 (s, 1H); 8.19 (s, 1H);7.89 (d, 2H); 7.74 (d, 2H); 4.17 (m, 2H); 3.91 (m, 2H); 3.75 (m, 3.75);3.27 (m, 2H); 3.02 (m, 6H); 2.66 (m, 1H); 2.07 (m, 2H); 1.87 (m, 2H);1.28 (m, 4H). LCMS (ESI) m/z 521 (M+H⁺, 100%)

Compound B321-[6-(2,2-Difluoro-benzo[1,3]dioxol-4-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. purified by preparatory TLC [SiO₂; EtOAc/hexane; 20:80].Yield 0.069 g, 74%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 10.06(s, 1H); 8.10 (s, 1H); 7.61 (s, 1H); 7.25 (s, 1H); 7.04 (m, 2H); 4.17(m, 2H); 3.91 (m, 2H); 3.25 (m, 2H); 2.65 (m, 1H); 2.05 (m, 2H); 1.87(m. 2H); 1.28 (m, 3H). LCMS (ESI) m/z 452 (M+H⁺, 100%)

Compound B331-[6-(2,2-Difluoro-benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Preparatory TLC [SiO2; EtOAc/hexane; 20:80]. Yield 0.048 g,50%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 9.87 (s, 1H); 8.13 (s,1H); 7.67 (m, 1H); 7.25 (s, 1H); 7.09 (m, 1H); 6.92 (m, 1H); 4.17 (m,2H); 3.92 (m, 2H); 3.26 (m, 2H); 2.66 (m, 1H); 2.06 (m, 2H); 1.88 (m,2H); 1.58 (m, 2H); 1.28 (m, 3H). LCMS (ESI) m/z 452 (M+H⁺, 100%)

Compound B341-[6-(1,1-Dioxo-1H-1λ⁶-benzo[b]thiophen-6-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. preparatory TLC [SiO2; EtOAc/hexane; 20:80]. Yield 0.021 g,22%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ (ppm): 10.23 (s, 1H); 8.35 (m,1H); 8.07 (s, 1H); 7.51 (m, 1H); 7.21 (m, 1H); 7.08 (m, 1H); 6.57 (m,1H); 4.05 (q, 2H); 3.79 (m, 2H); 3.13 (m, 2H); 2.53 (m, 1H); 1.93 (m,2H); 1.74 (m, 2H); 1.15 (m, 3H). LCMS (ESI) m/z 460 (M+H⁺, 100%)

Compound B351-{6-[(Furan-3-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 14]. HPLC provided compound B35 as yellow solid (46 mg, 61%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 8.71 (s, 1H); 8.16 (s, 1H); 7.44 (s, 1H); 7.37(d, 1H); 6.35 (d, 1H); 4.59 (d, 2H); 4.11 (q, 2H); 3.82 (dt, 2H); 3.26(td, 2H); 2.61 (m, 1H); 2.00 (dt, 2H); 1.84 (td, 2H); 1.20 (t, 3H).Exact mass calculated for C₁₇H₂₁N₅O₅ 375.15, LCMS (ESI) m/z 376.1 (M+H⁺,100%).

Compound B361-{6-[2-(4-Methoxy-phenoxy)-ethylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 14]. HPLC provided compound B36 as yellow solid (77 mg, 69%). ¹HNMR 400 MHz CDCl₃ δ (ppm): 9.22 (s, 1H); 8.26 (s, 1H); 6.90 (d, 2H);6.87 (d, 2H); 4.20 (t, 2H); 4.19 (t, 2H); 4.04 (q, 2H); 3.93 (dt, 2H);3.79 (s, 3H); 3.39 (Id, 2H); 2.72 (m, 1H); 2.11 (dt, 2H); 1.94 (td, 2H);1.30 (t, 3H). Exact mass calculated for C₂₁H₂₇N₅O₆ 445.20, LCMS (ESI)m/z 446.2 (M+H⁺, 100%).

Compound B371-{6-[2-(5-Methoxy-1H-indol-3-yl)-ethylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 14]. HPLC provided compound B37 as yellow solid (63 mg, 54%). ¹HNMR 400 MHz CDCl₃ δ (ppm): 8.47 (s, 1H); 8.04 (s, 1H); 7.91 (s, 1H);7.19 (d, 1H); 7.01 (dd, 2H); 6.80 (dd, 1H); 4.08 (q, 2H); 3.84 (dt, 2H);3.78 (s, 3H); 3.13 (td, 2H); 3.03 (t, 2H); 2.54 (m, 5H); 1.94 (dt, 2H);1.76 (td, 2H); 1.18 (t, 3H). Exact mass calculated for C₂₃H₂₈N₆O₅ 468.21(ESI) m/z 469.2, 100%).

Compound B38(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine

[Method 16]. preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.003 g,3%. Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 9.78 (s, 1H); 7.87 (s,1H); 6.85 (m, 1H); 6.74 (m, 1H); 4.00 (m, 4H); 3.71 (m, 2H); 2.86 (m,2H); 1.97 (m, 2H); 1.58 (m, 2H); 1.12 (m, 2H); 1.03 (m, 6H); 0.69 (m,3H). LCMS (ESI) m/z 414 (M+H⁺, 100%)

Compound B39(3-Fluoro-phenyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.007 g, 9%.Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 10.11 (s, 1H); 8.08 (s, 1H);7.59 (m, 1H); 7.26 (m, 1H); 7.20 (m, 1H); 6.82 (m, 1H); 3.90 (m, 2H);3.04 (m, 2H); 1.76 (m, 2H); 1.56 (m, 1H); 1.29 (m, 2H); 1.20 (m, 4H);0.86 (m, 3H). LCMS (ESI) m/z 360 (M+H⁺, 100%)

Compound B40(3-Methoxy-phenyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.002 g, 2%.Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 10.04 (s, 1H); 8.04 (s, 1H);7.21 (m, 2H); 7.04 (m, 1H); 6.67 (m, 1H); 3.87 (m, 2H); 3.75 (s, 3H);3.02 (m, 2H); 1.74 (m, 2H); 1.49 (m, 1H); 1.27 (m, 2H); 1.19 (m, 4H);0.84 (m, 3H). LCMS (ESI) m/z 404 (M+H⁺, 100%)

Compound B411-{6-[(3-Fluoro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.023 g, 30%.Light brown oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 8.13 (s, 1H); 7.26 (m,1H); 6.88 (m, 3H); 4.13 (q, 2H); 3.91 (m, 2H); 3.53 (s, 3H); 3.19 (m,2H); 2.58 (m, 1H); 1.99 (m, 2H); 1.81 (m, 2H); 1.24 (m, 3H). LCMS (ESI)m/z 404 (M+H⁺, 100%)

Compound B421-[6-(4-Benzoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 20:80]. Yield 0.059 g, 65%.Light yellow solid. ¹H NMR 400 MHz CDCl₃ δ□ (ppm): 10.31 (s, 1H); 8.21(s, 1H); 7.89 (m, 2H); 7.82 (m, 4H); 7.61 (m, 1H); 7.50 (m, 2H); 4.19(q, 2H); 3.94 (m, 2H); 3.27 (m, 2H); 2.67 (m, 1H); 2.08 (m, 2H); 1.89(m, 2H); 1.29 (m, 3H). LCMS (ESI) m/z 476 (M+H⁺, 100%)

Compound B431-{6-[4-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 50:50]. Yield 0.055 g, 56%.Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 10.09 (s, 1H); 8.11 (s, 1H);7.55 (d, 2H); 7.31 (d, 2H); 5.29 (s, 1H); 4.15 (m, 2H); 3.89 (m, 2H);3.63 (m, 2H); 3.22 (m, 2H); 3.01 (m, 6H); 2.64 (m, 1H); 2.03 (m, 2H);1.84 (m, 2H); 1.25 (m, 4H). LCMS (ESI) m/z 519 (M+H⁺, 100%)

Compound B441-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 50:50]. Yield 0.032 g, 37%.Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 10.21 (s, 1H); 8.11 (s, 1H);7.83 (m, 4H); 4.09 (m, 2H); 3.84 (m, 2H); 3.18 (m, 2H); 2.99 (s, 3H);2.59 (m, 1H); 1.98 (m, 2H); 1.79 (m, 2H); 1.20 (m, 3H). LCMS (ESI) m/z450 (M+H⁺, 100%)

Compound B451-[6-(4-Dimethylsulfamoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. The solvent was removed in vacuo and the residue purifiedby preparatory TLC [SiO₂; EtOAc/hexane; 40:60]. Yield 0.060 g, 57%.Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm): 10.20 (s, 1H); 8.10 (s, 1H);7.79 (d, 2H); 7.68 (d, 2H); 4.09 (q, 2H); 3.84 (m, 2H); 3.18 (m, 2H);2.64 (s, 6H); 2.57 (m, 1H); 1.98 (m, 2H); 1.79 (m, 2H); 1.20 (m, 3H).LCMS (ESI) m/z 479 (M+H⁺, 100%)

Compound B461-[6-(3-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. purified by preparatory TLC. [SiO₂; 2:3 EtOAc/hexanes].Yield 75 mg, 84%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 10.15(s, 1H); 8.16 (s, 1H); 7.24 (m, 2H); 7.11 (m, 1H); 6.88 (m, 1H); 4.10(q, 2H); 3.92 (m, 2H); 3.82 (s, 1H); 3.17 (m, 2H); 2.62 (heptet, 1H);2.09 (m, 2H); 1.95 (m, 2H); 1.25 (t, 3H). LCMS (PSI), m/z 401 (M+H⁺,100%)

Compound B471-[6-(2-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. purified by, preparatory TLC. [SiO₂; 15/85 EtOAc/hexanes].Yield 56 mg, 63%. Yellow solid, ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 10.57(s, 1H); 8.41 (m, 1H); 8.18 (s, 1H); 7.15 (m, 1H); 7.0 (m, 1H); 4.21 (q,2H); 3.92 (m, 5H); 3.25 (m, 2H); 2.63 (m, 2H); 2.08 (m, 2H); 1.88 (m,2H); 1.24 (m, 3H). LCMS (ESI), m/z 401 (M+H⁺, 100%)

Compound B481-[6-(3,5-Bis-trifluoromethyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Purified by flash chromatography. [Silica Gel 60; 20/80EtOAc/hexanes]. Yield 89 mg, 80%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃)δ (ppm): 10.23 (s, 1H); 8.20 (m, 3H); 7.65 (s, 1H); 4.20 (m, 2H); 3.92(m, 2H); 3.15 (m, 2H); 2.68 (heptet, 1H); 2.10 (m, 2H); 1.94 (m, 2H);1.30 (t, 3H). LCMS (ESI), m/z 507 (M+H⁺, 100%)

Compound B491-[6-(2,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. purified by preparatory TLC. [SiO₂; 20/80 EtOAc/hexanes].Yield 61 mg, 64%. Orange solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 10.61(s, 1H); 8.24 (s, 1H); 8.17 (s, 1H); 6.84 (d, 1H); 6.62 (dd, 1H); 4.17(q, 2H); 3.92 (m, 5H); 3.80 (s, 3H); 3.23 (m, 2H); 2.63 (heptet, 1H);2.10 (m, 2H); 1.84 (m, 2H); 1.25 (t, 3H). LCMS (ESI), m/z 431 (M+H⁺,100%)

Compound B501-[6-(3,5-Dimethoxy-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 14]. Semi preparatory HPLC afforded the pure product in 28%. ¹HNMR, 400 MHz, CDCl₃, δ (ppm): 8.85 (m, 1H); 8.32 (s, 1H); 7.50 (s, 1H);6.73 (d, 2H); 6.63 (t, 1H); 4.96 (d, 2H); 4.40 (q, 2H); 4.13 (m, 2H);4.03 (s, 6H); 3.45 (m, 2H); 2.86 (m, 1H); 2.26 (m, 2H); 2.08 (m, 2H);1.50 (t, 3H). LCMS (ESI) for C₂₂H₂₉N₅O₇: m/z 475 (M+H⁺, 100%).

Compound B51[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(3,4,5-trimethoxy-benzyl)-amine

[method 14]. semi preparative HPLC afforded the pure product in 16%. ¹HNMR, 400 MHz, CDCl₃, δ (ppm): 8.81 (m, 1H); 8.05 (s, 1H); 7.07 (s, 1H);6.39 (s, 2H); 4.53 (d, 2H); 3.76 (m, 1H); 3.67 (s, 6H); 3.66 (s, 3H);3.01 (m, 2H); 1.68 (d, 2H); 1.12 (m, 6H); 0.72 (t, 3H). LCMS (ESI) forC₂₂H₃₁N₅O₅: m/z 445 (M+H⁺, 100%).

Compound B52(3,5-Dimethoxy-benzyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine

[method 14]. Semi preparative HPLC afforded the pure product in 20%. ¹HNMR, 400 MHz, CDCl₃, δ (ppm): 8.66 (m, 1H); 8.11 (s, 1H); 7.30 (s, 1H);6.54 (d, 2H); 6.43 (t, 1H); 4.76 (d, 2H); 3.96 (m, 1H); 3.83 (s, 6H);3.12 (m, 2H); 1.84 (m, 2H); 1.38 (m 2H); 1.30 (m 4H); 0.95 (t, 3H). LCMS(ESI) for C₂₁H₂₉N₅O₄: m/z 415 (M+H⁺, 100%).

Compound B53(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-ylamino}-phenyl)-phenyl-methanone

[Method 16]. purified by preparative TLC. [SiO₂; 30/70 EtOAc/hexanes].Yield 42 mg, 51%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 10.3 (s,1H); 8.44 (d, 1H); 8.20 (s, 1H); 7.87 (m, 2H); 7.81 (m, 4H); 7.59 (m,1H); 7.50 (m, 3H); 7.18 (d, 1H); 7.01 (d, 1H); 4.22 (heptet, 1H); 3.92(m, 2H); 3.45 (dt, 2H); 2.26 (m, 2H); 1.86 (m, 2H). LCMS (ESI), m/z 513(M+H+, 100%)

Compound B54(4-{5-Nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidin-4-ylamino}-phenyl)-phenyl-methanone

[Method 16]. residue purified by preparatory TLC [SiO₂; EtOAc/hexane;20:80]. Yield 0.057 g, 68%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm):10.24 (s, 1H); 8.13 (s, 1H); 7.80 (m, 2H); 7.74 (m, 4H); 7.52 (m, 2H);7.42 (m, 4H); 6.95 (m, 2H); 4.78 (m, 1H); 3.64 (m, 4H); 2.02 (m, 4H).LCMS (ESI) m/z 564 (M+H⁺, 100%)

Compound B551-[6-(4-Cyano-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. residue purified by preparatory TLC [SiO₂; EtOAc/hexane;20:80]. Yield 0.035 g, 40%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm):10.19 (s, 1H); 8.10 (s, 1H); 7.76 (d, 2H); 7.58 (d, 2H); 4.09 (q, 2H);3.83 (m, 2H); 3.17 (m, 2H); 2.58 (m, 1H); 1.97 (m, 2H); 1.78 (m, 2H);1.19 (m, 3H) LCMS (ESI) m/z 397 (M+H⁺, 100%)

Compound B561-[6-(3,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. residue purified by preparatory TLC [SiO₂; EtOAc/hexane;20:80]. Yield 0.070 g, 73%. Orange solid. ¹H NMR 400 MHz CDCl₃ δ□(ppm):9.84 (s, 1H); 7.91 (s, 1H); 6.60 (d, 2H); 6.10 (t, 1H); 3.954 (q, 2H);3.69 (m, 2H); 3.58 (s, 6H); 3.01 (m, 2H); 2.42 (m, 1H); 1.82 (m, 2H);1.63 (m, 2H); 1.05 (m, 3H). LCMS (ESI) m/z 432 (M+H⁺, 100%)

Compound B571-[6-(4-sec-Butyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. residue purified by preparatory TLC [SiO₂; EtOAc/hexane;20:80]. Yield 0.088 g, 93%. Orange oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm):10.10 (s, 1H); 8.14 (s, 1H); 7.50 (d, 2H); 7.21 (d, 2H); 4.19 (q, 2H);3.94 (m, 2H); 3.26 (m, 2H); 2.63 (m, 2H); 2.06 (m, 2H); 1.87 (m, 2H);1.61 (m, 2H); 1.27 (m, 6H); 0.86 (m, 3H). LCMS (ESI) m/z 428 (M−H⁺,100%)

Compound B581-[6-(4-Heptyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. residue purified by preparatory TLC [SiO₂; EtOAc/hexane;20:80]. Yield 0.092 g, 89%. Orange oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm):10.05 (s, 1H); 8.09 (s, 1H); 7.43 (d, 2H); 7.18 (d, 2H); 4.16 (q, 2H);3.90 (m, 2H); 3.22 (m, 2H), 2.60 (m, 3H); 2.02 (m, 2H); 1.84 (m, 2H);1.27 (m, 13H); 0.87 (m, 3H). LCMS (ESI) m/z 470 (M+H⁺, 100%)

Compound B592′-(4-Benzoyl-phenylamino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylicacid ethyl ester. General Method 17

A mixture of 2,4-dichloro-3-nitro-pyridine (77 mg, 0.4 mmol),4-benzoyl-aniline (1.0 eqv, 7 9 mg, 0.4 mmol) and potassium carbonate(1.4 eqv, 78 mg, 0.56 mmol) in DMF (1 ml) was stirred in a sealed vesselat 150° C. for 30 mins under microwave irradiation. HPLC providedintermediate compound 2-[4-benzoyl-anilino]-4-dichloro-3-nitro-pyridineas brown solid (58 mg, 41% yield). Exact mass calculated forC₁₈H₁₂ClN₃O₃ 353.06, LCMS (ESI) m/z 353.6 (M+H⁺, 100%).

[method 14]. RP-HPLC provided compound B59 as orange solid (26 mg, 27%yield). ¹H NMR 400 MHz CDCl₃ δ (ppm): 9.55 (s, 1H); 7.89 (d, 3H); 7.74(d, 2H); 7.57 (t, 1H); 7.46 (t, 2H); 7.32 (d, 2H); 6.50 (d, 1H); 4.12(q, 2H); 3.63 (d, 2H); 3.26 (t, 2H); 2.63-2.58 (m, 1H); 2.04 (d, 2H);1.94 (td, 2H); 1.21 (t, 3H). Exact mass calculated for C₂₆H₂₆N₄O₅474.19, LCMS (ESI) m/z 475.3 (M+H⁺, 100%).

Compound B601-[5-Nitro-6-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. purified by preparatory TLC. [SiO₂; 30/70 EtOAc/hexanes].Yield 42 mg, 41%. Orange oil. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 9.97 (s,1H); 8.05 (s, 1H); 6.77 (s, 2H); 4.08 (q, 2H); 3.81 (m, 11H); 3.17 (t,2H); 2.58 (heptet, 1H); 1.97 (t, 2H); 1.78 (q, 2H); 1.19 (t, 3H). LCMS(ESI), m/z 462 (M+H+, 100%)

Compound B611-[5-Nitro-6-(4-pentyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. purified by preparatory TLC. [SiO₂; 20/80 EtOAc/hexanes].Yield 79 mg, 81%. Yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 9.99 (s,1H); 8.00 (s, 1H); 7.38 (d, 2H); 7.12 (d, 2H); 4.09 (q, 2H); 3.83 (m,2H); 3.15 (m, 2H); 2.55 (m, 3H); 1.95 (m, 2H); 1.79 (m, 2H); 1.53 (m,2H); 1.24 (m, 7H); 0.81 (t, 3H). LCMS (ESI), m/z 442 (M+H⁺, 100%)

Compound B621-{6-[4-(3-Carboxy-propyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. purified by preparatory TLC. [SiO₂; 30/70 EtOAc/hexanes].Yield 67 mg, 67%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 10.08(s, 1H); 8.13 (s, 1H); 7.49 (d, 2H); 7.22 (d, 2H); 4.18 (q, 2H); 3.92(m, 2H); 3.25 (m, 2H); 2.68 (m, 3H); 2.40 (t, 2H); 2.06 (m, 2H); 1.96(m, 2H); 1.88 (m, 2H); 1.27 (t, 3H). LCMS (ESI), m/z 458 (M+H⁺, 100%)

Compound B631-{6-[4-(Cyano-phenyl-methyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Dry crude B63 was purified by Biotage Horizon 2 [12+Mcolumn; 30/70 EtOAc/hexanes]. Yield 93 mg, 87%. Yellow film. ¹H-NMR (400MHz, CDCl₃) δ(ppm): 10.13 (s, 1H); 8.13 (s, 1H); 7.64 (tt, 2H); 7.36 (m,7H); 5.31 (s, 1H); 4.17 (q, 2H); 3.92 (m, 2H); 3.25 (m, 2H); 2.66(heptet, 1H); 2.06 (m, 2H); 1.88 (m, 2H); 1.28 (t, 3H). LCMS (ESI), m/z486 (M+H⁺, 100%)

Compound B641-[6-(4-Cyclohexyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Crude B64 was purified by preparatory TLC [SiO2; 20/80EtOAc/hexanes]. Yield 55 mg, 55%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃)δ(ppm): 9.99 (s, 1H); 8.04 (s, 1H); 7.38 (tt, 2H); 7.16 (m, 2H); 4.09(m, 2H); 3.84 (m, 2H); 3.16 (m, 2H); 2.56 (heptet, 1H); 2.43 (m, 1H);1.95 (m, 2H); 1.79 (m, 8H); 1.31 (m, 2H), 1.20 (1, 5H). LCMS (ESI), m/z453 (M+H⁺, 100%)

Compound B651-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Crude B65 was purified by flash chromatography [Silica Gel60; 30/70 EtOAc/hexanes]. Yield 53 mg, 55%. Yellow solid. ¹H-NMR (400MHz, CDCl₃) δ(ppm): 10.42 (s, 1H); 8.56 (s, 1H); 8.15 (s, 1H); 8.11 (s,1H); 7.79 (tt, 2H); 7.71 (tt, 2H); 4.17 (q, 2H); 3.93 (m, 2H); 3.26 (m,2H); 2.66 (heptet, 1H); 2.05 (m, 2H); 1.87 (m, 2H); 1.27 (m, 3H). LCMS(ESI), m/z 438 (M+H⁺, 100%)

Compound B661-[5-Nitro-6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Purified by flash chromatography [Silica Gel 60; 30/70EtOAc/hexanes]. Yield 34 mg, 31%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃)δ(ppm): 10.72 (s, 1H); 8.16 (s, 1H); 7.98 (m, 4H); 4.10 (q, 2H); 3.85(m, 2H); 3.20 (m, 2H); 2.60 (heptet, 1H); 1.99 (m, 2H); 1.81 (m, 2H);1.19 (m, 3H). LCMS (ESI), m/z 503 (M+H⁺, 100%)

Compound B671-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. purified by flash chromatography [Silica Gel 60; 30/70EtOAc/hexanes]. Yield 39 mg, 39%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃)δ (ppm): 10.48 (s, 1H); 8.65 (s, 1H); 8.18 (s, 1H); 8.08 (tt, 2H); 7.80(tt, 2H); 4.16 (q, 2H); 3.94 (m, 2H); 3.26 (m, 2H); 2.66 (heptet, 1H);2.06 (m, 2H); 1.89 (m, 2H); 1.28 (t, 3H).

Compound B68[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine

[Method 16]. purified by HPLC [Semi-Prep]. Yield 13 mg, 17%. Yellowsolid. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 10.13 (s, 1H); 7.99 (s, 1H); 7.73(m, 4H); 3.79 (m, 2H); 3.3 (q, 2H); 3.11 (d, 2H); 2.95 (m, 2H); 2.86 (s,3H); 1.77 (m, 3H); 1.18 (m, 2H); 1.02 (m, 3H). LCMS (ESI), m/z 436(M+H⁺, 100%)

Compound B69[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine

[Method 16]. purified by preparatory TLC [SiO₂; 50/50 EtOAc/hexanes].Yield 27 mg, 27%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 10.17(s, 1H); 8.47 (s, 1H); 8.07 (s, 1H); 8.04 (s, 1H); 7.73 (tt, 2H); 7.63(tt, 2H); 3.89 (m, 2H); 3.05 (m, 2H); 1.76 (m, 2H); 1.40 (m, 1H); 1.24(m, 6H); 0.85 (t, 3H). LCMS (ESI), m/z 408 (M+H⁺, 100%)

Compound B70{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine

-   [Method 16]. The crude was purified by HPLC. Yield 52 mg, 55%.    Yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 10.18 (s, 1H); 8.47    (s, 1H); 8.37 (m, 1H); 8.09 (s, 1H); 8.04 (s, 1H); 7.72 (tt, 2H);    7.63 (tt, 2H); 7.43 (ddd, 1H); 7.12 (tt, 1H); 6.94 (m, 1H); 4.15    (heptet, 1H); 3.85 (m, 2H); 3.37 (m, 2H); 2.19 (m, 2H); 1.79 (m,    2H). LCMS (ESI), m/z 476 (M+H⁺, 100%)

Compound B71(2-Fluoro-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine

[Method 16]. Purified by HPLC. Yield 33 mg, 38%. Yellow solid. ¹H-NMR(400 MHz, CDCl₃) δ (ppm): 10.01 (s, 1H); 8.09 (s, 1H); 7.63 (t, 1H);7.28 (m, 1H); 7.16 (m, 2H); 3.98 (m, 2H); 3.41 (m, 2H); 3.33 (heptet,1H); 2.36 (s, 3H); 2.23 (m, 2H); 2.05 (m, 2H). LCMS (ESI), m/z 399(M+H⁺, 100%)

Compound B72(4-Methanesulfonyl-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine

[Method 16]. yellow solid. Yield 15.2%. ¹H NMR 400 MHz CDCl₃ δ (ppm):10.5 (s, 1H); 8.49 (s, 1H); 8.2 (dd, 4H); 4.26 (d, 2H); 3.64 (m, 2H);3.60 (m, 1H); 3.33 (s, 3H); 2.67 (s, 3H); 2.5 (d, 2H); 2.33 (m, 2H).LCMS (ESI) m/z 460.2 (M⁺H⁺, 100%)

Compound B73{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine

[Method 16]. yellow solid. Yield 11%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 10(s, 1H); 8.41 (s, 1H); 8.02 (s, 1H); 7.97 (s, 1H); 7.64 (d, 2H); 7.55(d, 2H); 3.84 (d, 2H); 3.24 (m, 2H); 3.20 (m, 1H); 2.25 (s, 3H); 2.09(d, 2H); 1.90 (m, 2H). LCMS (ESI) m/z 449.2 (M⁺H⁺, 100%)

Compound B741-{5-Nitro-6-[4-(4-trifluoromethyl-phenoxy)-phenylamino]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. residue purified by preparatory TLC [SiO2; EtOAc/hexane;20:80]

Yield 0.057 g, 56%. Yellow solid. ¹H NMR 400 MHz CDCL₃ δ□(ppm): 10.23(s, 1H); 8.25 (s, 1H); 7.72 (m, 4H); 7.20 (m, 4H); 4.30 (q, 2H); 4.05(m, 2H); 3.37 (m, 2H); 2.78 (m, 1H); 2.18 (m, 2H); 2.00 (m, 2H); 1.40(m, 3H). LCMS (ESI) m/z 532 (M+H⁺, 100%)

Compound B75{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-phenyl)-amine

[Method 16]. The desired product was observed by LCMS m/z 414 (M+H⁺.Purification by RP-HPLC. Yield 69%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 10.00(s, 1H); 8.11 (s, 1H); 8.09 (m, 1); 7.12 (m, 3H); 3.97 (d, 2H); 3.29 (m,2H); 3.26 (m, 1H); 2.69 (m, 2H); 2.18 (m, 2H); 2.06 (m, 2H); 1.29 (t,3H). LCMS (ESI) m/z 414 (M+H⁺, 100%)

Compound B76{6-[4-(2-Methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine

[Method 16]. Yield 43%. Yellow solid. ¹H NMR 400 MHz CDCl₃ δ (ppm): 9.98(s, 1H); 8.33 (s, 1H); 7.91 (d, 2H); 7.57 (d, 2H); 7.47 (d, 2H); 7.20(m, 1H); 7.09 (m, 2H); 6.70 (m, 2H); 3.69 (s, 3H); 3.33 (m, 1H); 3.10(m, 2H); 1.85 (m, 2H); 1.51 (m, 4H). LCMS (ESI) m/z 505 (M+H⁺, 100%)

Compound B77(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine

Crude B77 was purified by flash chromatography [Silica gel 60; 50/50EtOAc/hexanes]. Yield 49 mg, 50%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃)δ(ppm): 10.25 (s, 1H); 8.13 (s, 1H); 7.85 (m, 4H); 7.64 (tt, 1H); 7.43(m, 1H); 7.11 (d, 1H); 6.95 (m, 1H); 4.15 (m, 1H); 3.85 (m, 2H); 3.38(m, 2H); 2.99 (s, 3H); 2.19 (m, 2H); 1.79 (m, 2H). LCMS (ESI), m/z 487(M+H⁺, 100%)

Compound B78(3-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine

[Method 16]. The crude mixture was purified by preparatory TLC [SiO₂;20/80 EtOAc/hexanes].

Yield 70 mg, 87%. Yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 10.25(s, 1H); 8.55 (m, 1H); 8.25 (s, 1H); 7.60 (ddd, 1H); 7.40 (m, 2H); 7.38(s, 1H); 7.29 (d, 1H); 7.22 (d, 1H); 7.12 (m, 1H); 4.33 (heptet, 1H);4.01 (m, 2H); 3.94 (s, 3H); 3.54 (m, 2H); 2.36 (m, 2H); 1.98 (m, 2H).LCMS (ESI), m/z 439 (M+H⁺, 100%)

Compound B79Benzo[1,3]dioxol-5-yl-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine

[Method 16]. Residue purified by preparatory TLC [SiO₂; EtOAc/hexane;20:80]. Yield 0.005 g, 6%. Yellow oil. ¹H NMR 400 MHz CDCl₃ δ□(ppm):9.92 (s, 1H); 8.01 (s, 1H); 7.13 (m, 1H); 6.78 (m, 1H); 6.72 (m, 1H);5.92 (s, 2H); 3.87 (m, 2H); 3.02 (m, 2H); 1.74 (m, 2H); 1.48 (m, 1H);1.27 (m, 2H); 1.18 (m, 4H); 0.84 (m, 3H). LCMS (ESI) m/z 386 (M+H⁺,100%)

Compound B80(4-Fluoro-phenyl)-{1-[5-nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidin-4-yl}-methanone

Purification by HPLC. Yield 56%. yellow solid TFA salt. ¹H NMR 400 MHzCDCl₃ δ (ppm): 11.61 (s, 3H); 10.3 (s, 1H); 9.18 (s, 1H); 8.39 (s, 1H);8.18 (s, 1H); 8.01 (m, 2H); 7.84 (d, 2H); 7.74 (d, 2H); 7.19 (t, 2H);4.07 (d, 2H); 3.67 (m, 1H); 3.47 (m, 2H); 2.05 (m, 4H). LCMS (ESI) m/z489.4 (M⁺H⁺, 100%)

Compound B81[5-Nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine

[Method 16]. product precipitated from the crude as a yellow solid. Itwas filtered and washed with hexane. Yield 36%. ¹H NMR 400 MHz CDCl₃ δ(ppm): 10.17 (s, 1H); 8.57 (s, 1H); 8.10 (d, 2H); 7.76 (d, 2H); 7.66 (d,2H); 7.42 (m, 2H); 7.29 (m, 3H); 3.89 (m, 2H); 3.39 (m, 1H); 3.27 (m,2H); 2.06 (m; 2H); 1.71 (m, 2H). LCMS (ESI) m/z 475.3 (M⁺H⁺, 100%)

Compound B82(4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone

[Method 16]. Purification by HPLC. Yield 17%. red oil. ¹H NMR 400 MHzCDCl₃ δ (ppm): 9.92 (s, 1H); 7.96 (s, 1H); 7.79 (m, 2H); 7.46 (m, 1H);7.17 (m, 1H); 7.02 (m, 4H); 3.86 (d, 2H); 3.46 (m, 1H); 3.31 (m, 2H);1.86 (m, 4H). LCMS (ESI) m/z 440.4 (M⁺H⁺, 100%)

Compound B831-[6-(2-Methyl-5-phenyl-2H-pyrazol-3-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. Purification by HPLC yielded orange solid. Yield 30%. ¹HNMR 400 MHz CDCl₃ δ (ppm): 8.34 (s, 1H); 7.90 (m, 2H); 7.68 (d, 3H);7.04 (s, 1H); 4.32 (m, 2H); 4.11 (s, 3H); 4.06 (m, 2H); 3.44 (m, 2H);2.83 (m, 1H); 2.22 (m, 2H); 2.04 (m, 2H); 1.41 (1, 3H). LCMS (ESI) m/z452 (M⁺H⁺, 100%)

Compound B84(4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-amine

[Method 16]. Purification by HPLC yielded yellow solid. Yield 9%. ¹H NMR400 MHz CDCl₃ δ (ppm): 10.0 (s, 1H); 8.00 (s, 1H); 7.75 (d, 2H); 7.68(d, 2H); 7.26 (m, 2H); 7.14 (m, 3H); 3.73 (d, 2H); 3.22 (m, 1H); 3.13(m, 2H); 2.87 (s, 3H); 1.91 (m, 2H); 1.55 (m, 2H). LCMS (ESI) m/z 486(MIT, 100%)

Compound B85(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine

[Method 16]. as yellow solid (68 mg, 72%). ¹H NMR 400 MHz CDCl₃ δ(ppm):10.2 (s, 8.13 (s, 1H); 8.12 (d, 1H); 7.87 (d, 2H); 7.83 (d, 2H); 7.60(t, 1H); 6.87 (t, 1H); 6.73 (d, 1H); 5.29 (m, 1H); 3.76-3.70 (m, 2H);3.56-3.51 (m, 2H); 2.99 (s, 3H); 2.10-2.05 (m, 2H); 1.95-1.90 (m, 2H).Exact mass calculated for C₂₁H₂₂N₆O₅S 470.14, LCMS (ESI) m/z 471.4(M+H⁺, 100%).

Compound B86{6-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine

[method 16] afforded compound B86 as yellow solid (58 mg, 60%). ¹H NMR400 MHz CDCl₃ δ(ppm): 10.2 (s, 1H); 8.13 (s, 1H); 7.87 (d, 2H); 7.81 (d,2H); 6.92 (m, 2H); 6.82 (m, 2H); 4.50 (m, 1H); 3.71-3.65 (m, 2H);3.54-3.51 (m, 2H); 2.99 (s, 3H); 1.99-1.91 (m 2H). Exact mass calculatedfor C₂₂H₂₂FN₅O₅S 487.13, LCMS (ESI) m/z 488.3 (M+H⁺, 100%).

Compound B87(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine

Method 16 afforded compound B87 as yellow solid (56 mg, 60%). ¹H NMR 400MHz CDCl₃ δ(ppm): 10.2 (s, 1H); 8.68 (d, 2H); 8.17 (s, 1H); 7.88 (d,2H); 7.83 (d, 2H); 7.26 (d, 2H); 4.96 (m, 1H); 3.76-3.69 (m, 2H);3.62-3.57 (m, 2H); 3.00 (s, 3H); 2.21-2.15 (m 2H); 2.03-1.99 (m, 2H).Exact mass calculated for C₂₁H₂₂N₆O₅S 470.14, LCMS (ESI) m/z 471.2(M+H⁺, 100%).

Compound B88(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyrimidin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine

Method 16 afforded compound B88 as a yellow solid (69 mg, 73%). ¹H NMR400 MHz CDCl₃ δ(ppm): 10.2 (s, 1H); 8.52 (d, 2H); 8.14 (s, 1H); 7.88 (d,2H); 7.83 (d, 2H); 6.96 (t, 1H); 5.34 (m, 1H); 3.79-3.72 (m, 2H);3.58-3.52 (m, 2H); 2.99 (s, 3H); 2.14-2.08 (m 2H); 2.02-1.93 (m, 2H).Exact mass calculated for C₂₀H₂₁N₇O₅S 471.13, LCMS (ESI) m/z 472.0(M+H⁺, 100%).

Compound B89(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine

Method 16 afforded compound B89 as a yellow solid (52 mg, 54%). ¹H NMR400 MHz CDCl₃ δ(ppm); 10.1 (s, 1H); 8.56 (d, 2H); 8.17 (s, 1H); 7.89 (d,2H); 7.83 (d, 2H); 7.53 (d, 2H); 3.92-3.89 (m, 2H); 3.84 (m, 1H);3.44-3.38 (m, 2H); 3.00 (s, 3H); 2.26-2.22 (m 2H); 1.94-1.88 (m, 2H).Exact mass calculated for C₂₁H₂₂N₆O₄S₂ 486.11, LCMS (ESI) m/z 487.2(M+H⁺, 100%).

Compound B90(4-Methanesulfonyl-phenyl)-{6-[4-(4-methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine

Method 16 afforded compound B90 as a as yellow solid (50 mg, 49%). ¹HNMR 400 MHz CDCl₃ δ(ppm): 10.2 (s, 1H); 8.11 (s, 1H); 7.87 (d, 2H); 7.80(d, 2H); 7.34 (d, 2H); 6.79 (d, 2H); 3.86-3.83 (m, 2H); 3.74 (s, 3H);3.22-3.12 (m, 3H); 2.99 (s, 3H); 1.99-1.95 (m 2H); 1.66-1.57 (m, 2H).Exact mass calculated for C₂₃H₂₅N₅O₅S₂ 515.13, LCMS (ESI) m/z 516.1(M+H⁺, 100%).

Compound B91[6-(4-Benzenesulfonyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine

Method 16 afforded compound B91 a as yellow solid (51 mg, 50%). ¹H NMR400 MHz CDCl₃ δ(ppm): 10.2 (s, 1H); 8.12 (s, 1H); 7.87 (d, 2H); 7.81 (d,2H); 7.79 (d, 2H); 7.64 (t, 1H); 7.53 (t, 1H); 4.01 (m, 2H); 3.17 (m,1H); 3.08-3.04 (m, 2H); 2.99 (s, 3H); 2.08-2.04 (m 2H); 1.82-1.78 (m,2H). Exact mass calculated for C₂₂H₂₃N₅O₆S₂ 517.11, LCMS (ESI) m/z 518.3(M+H⁺, 100%).

Compound B92{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperazin-1-yl}-aceticacid ethyl ester

[Method 16]. afforded compound 1392 as a yellow solid (45 mg, 48%). 400MHz CDCl₃ δ (ppm): 10.2 (s, 1H); 8.18 (s, 1H); 7.88 (d, 2H); 7.81 (d,2H); 4.21 (q, 2H); 3.86-3.83 (m, 6H); 3.46-3.43 (m, 4H); 3.00 (s, 3H);1.23 (t, 3H). Exact mass calculated for C₁₉H₂₄N₆O₆S 464.15, LCMS (ESI)m/z 465.3 (M+H⁺, 100%).

Compound B93(2-Fluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-cyclohexyl]-pyrimidin-4-yl}-amine

[Method 16]. The crude was dissolved in dichloromethane and purified bypreparative TLC. [SiO₂; 15/85 EtOAc/hexanes]. Yellow solid. Yield 7 mg,10%. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 10.07 (s, 1H); 8.37 (d, 1H); 8.13(m, 1H); 8.08 (s, 1H); 7.43 (ddd, 1H); 7.07 (m, 4H); 6.94 (m, 1H); 4.15(heptet, 1H); 3.85 (m, 2H); 3.36 (m, 2H); 2.18 (m, 2H); 1.79 (m, 2H).LCMS (ESI), m/z 427 (M+H⁺, 100%)

Compound B94(2-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-cyclohexyl]-pyrimidin-4-yl}-amine

[Method 16]. purified by preparative TLC. [SiO2; 15/85 EtOAc/hexanes].Yellow solid. Yield 42 mg, 56%. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 10.51(s, 1H); 8.36 (d, 2H); 8.10 (s, 1H); 7.42 (ddd, 1H); 7.10 (d, 1H); 7.03(ddd, 1H); 6.87 (d, 1H); 4.14 (heptet, 1H); 3.85 (m, 5H); 3.35 (m, 2H);2.17 (m, 2H); 1.78 (m, 2H). LCMS (ESI), m/z 438 (M+H+, 100%)

Compound B95(4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine

Following the general procedure 16, compound B95 was obtained as ayellow solid (61%). ¹H NMR (CDCl₃, 400 MHz) δ 2.06-2.10 (m, 2H),2.23-2.27 (m, 2H), 2.99 (s, 3H), 3.31-3.38 (m, 3H), 3.96-3.99 (m, 2H),7.55 (t, 1H), 7.70 (d, 1H), 7.86 (dd, 4H), 8.16 (s, 1H), 8.20 (d, 1H),8.28 (s, 1H), 10.2 (s, 1H). Exact mass calculated for C₂₅H₂₂F₃N₇O₅S589.1, found 590.4 (MH⁺).

Compound B96{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine

Following the general procedure 16, compound B96 was obtained as ayellow solid (31%). ¹H NMR (CDCl₃, 400 MHz) δ 1.25 (t, 3H), 2.06-2.10(m, 2H), 2.23-2.27 (m, 2H), 2.70 (q, 2H), 2.99 (s, 3H), 3.31-3.38 (m,3H), 3.96-3.99 (m, 2H), 7.84 (dd, 4H), 8.14 (s, 1H), 10.2 (s, 1H). Exactmass calculated for C₂₀H₂₃N₇O₅S 473.1, found 474.2 (MH⁺).

Compound B97(6-{4-[5-(4-Fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-piperidin-1-yl}-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine

Following the general procedure 16, compound B97 was obtained as ayellow solid (93%). ¹H NMR (CDCl₃, 400 MHz) δ 2.06-2.10 (m, 2H),2.23-2.27 (m, 2H), 2.99 (s, 3H), 331-3.38 (m, 3H), 3.96-3.99 (m, 2H),7.24 (dd, 2H), 7.96 (dd, 4H), 8.04-8.08 (m, 2H), 8.25 (s, 1H), 10.3 (s,1H). Exact mass calculated for C₂₄H₂₂FN₇O₅S 539.14, found 540.3 (MH⁺).

Compound B98(4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-pyridin-2-ylmethyl-piperidin-1-yl)-pyrimidin-4-yl]-amine

Following the general procedure 16, Compound B98 was obtained as ayellow solid (95%). ¹HNMR (CDCl₃, 400 MHz) δ 1.36-1.47 (m, 2H),1.69-1.72 (m, 2H), 2.12-2.18 (m, 1H), 2.99 (s, 3H), 3.00-3.05 (m, 2H),3.91-3.94 (m, 2H), 7.52 (d, 1H), 7.65 (dt, 1H), 7.85 (dd, 4H), 8.11 (s,1H), 8.17 (dt, 1H), 8.82 (d, 1H), 10.2 (s, 1H). Exact mass calculatedfor C₂₂H₂₄N₆O₄S 468.1, found 469.4 (MH⁺).

Compound B994-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile

Following the general procedure, Compound B99 was prepared. ¹H-NMR(DMSO-d₆): 9.38 (1H, s), 8.21 (1H, s), 7.47 (2H, J=4.3 Hz, d), 7.23 (2H,J=4.3 Hz, d), 4.50 (2H, m), 3.35 (2H, m), 3.02 (1H, m), 2.51 (3H, s),2.18 (2H, m), 1.79 (2H, m) 1.83 (6H, J=7 Hz, d) ppm. LCMS: 436.3, 351.9,324.4, 270.2.

Compound B1001-{6-[4-(4,5-Dichloro-imidazol-1-yl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. yellow solid (40 mg, 49%). ¹HNMR (CDCl₃, 400 MHz) δ 1.28(t, 3H), 1.87 (m, 2H), 2.06 (m, 2H), 2.66 (m, 1H), 3.26 (t, 2H), 3.93(m, 2H), 4.17 (q, 2H), 7.37 (m, 2H), 7.54 (s, 1H), 7.82 (m, 2H), 8.17(s, 1H), 10.23 (s, 1H). Exact mass calculated for C₂₁H₂₁Cl₂N₇O₄ 506.34,found 506.2 (MH⁺).

Compound B101Benzo[1,3]dioxol-5-yl-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine

[Method 16]. orange solid (9 mg, 14%). ¹HNMR (CDCl₃, 400 MHz) δ 1.78 (m,2H), 2.17 (m, 2H), 3.35 (m, 2H), 3.83 (m, 2H), 4.14 (m, 1H), 5.92 (m,2H), 6.75 (m, 2H), 6.94 (m, 1H), 7.11 (m, 1H), 7.19 (m, 1H), 7.42 (m,1H), 8.02 (s, 1H), 8.36 (m, 1H), 9.91 (s, 11-1). Exact mass calculatedfor C₂₄H₂₄N₄O₈S 452.49, found 453.2 (MH⁺).

Compound B102(4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone

[Method 16]. yellow solid (16 mg, 44%). ¹HNMR (CDCl₃, 400 MHz) δ 1.89(m, 4H), 3.26 (m, 2H), 3.51 (m, 1H), 3.96 (m, 2H), 7.10 (m, 5H), 7.92(m, 2H), 8.08 (s, 1H), 8.13 (m, 1H), 10.06 (s, 1H). Exact masscalculated for C₂₄H₂₄N₄O₈S 439.41, found 440.3 (MH⁺).

Compound B103{1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-(4-fluoro-phenyl)-methanone

[Method 16]. orange solid (20 mg, 53%). ¹HNMR (CDCl₃, 400 MHz) δ 1.89(m, 4H), 3.26 (m, 2H), 3.51 (m, 1H), 3.96 (m, 2H), 5.92 (s, 2H), 6.76(m, 2H), 7.10 (m, 3H), 7.92 (m, 2H), 8.03 (s, 1H), 9.91 (s, 1H). Exactmass calculated for C₂₃H₂₀FN₅O₅ 465.43, found 466.3 (MH⁺).

Compound B104(2,3-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine

[Method 16]. yellow solid (5 mg, 8%). ¹HNMR (CDCl₃, 400 MHz) δ 1.78 (m,2H), 2.17 (m, 2H), 3.35 (m, 2H), 3.83 (m, 2H), 4.14 (m, 1H), 6.94 (m,2H), 7.03 (m, 1H), 7.10 (m, 1H), 7.42 (m, 1H), 7.89 (m, 1H), 8.08 (s,1H), 8.37 (m, 1H), 10.05 (s, 1H). Exact mass calculated forC20H₁₈F₂N₆O₂S 444.46, found 444.9 (M+H⁺).

Compound B105(2,4-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine

[Method 16]. yellow solid (12 mg, 19%), ¹HNMR (CDCl₃, 400 MHz) δ 1.78(m, 2H), 2.17 (m, 2H), 3.35 (m, 2H), 3.83 (m, 2H), 4.14 (m, 1H), 6.85(m, 2H), 6.93 (m, 1H), 7.10 (m, 1H), 7.42 (m, 1H), 7.89 (m, 1H), 8.05(s, 1H), 8.37 (m, 1H), 9.91 (s, 1H). Exact mass calculated forC₂₀H₁₈F₂N₆O₂S 444.46, found 445.4 (M+H⁺).

Compound B106(2,5-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine

[Method 16]. yellow solid (3 mg, 5%), ¹HNMR (CDCl₃, 400 MHz) δ 1.78 (m,2H), 2.17 (m, 2H), 3.35 (m, 2H), 3.83 (m, 2H), 4.14 (m, 1H), 6.73 (m,1H), 6.93 (m, 1H), 7.03 (m, 1H), 7.11 (m, 1H), 7.42 (m, 1H), 8.13 (s,1H), 8.25 (m, 1H), 8.37 (m, 1H), 10.25 (s, 1H). Exact mass calculatedfor C₂₀H₁₈F₂N₆O₂S 444.46, found 445.3 (M+H⁺).

Compound B1071-[6-(4-Benzenesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. yellow solid (32 mg, 39%). ¹HNMR (CDCl₃, 400 MHz) δ 1.22(t, 3H), 1.80 (m, 2H), 2.00 (m, 2H), 2.60 (m, 1H), 3.20 (t, 2H), 3.85(m, 2H), 4.12 (q, 2H), 7.48 (m, 3H), 7.78 (d, 2H), 7.90 (m, 4H), 8.11(s, 1H), 10.19 (s, 1H). Exact mass calculated for C₂₄H₂₅N₅O₆S 511.55,found 512.3 (MH⁺).

Compound B1081-[5-Nitro-6-(2-trifluoromethyl-3H-benzoimidazol-5-ylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[Method 16]. yellow solid (11 mg, 14%). ¹HNMR (CDCl₃, 400 MHz) δ 1.40(t, 3H), 2.00 (m, 2H), 2.18 (m, 2H), 2.79 (m, 1H), 339 (t, 2H), 4.06 (m,2H), 4.30 (q, 2H), 7.43 (m, 1H), 7.65 (m, 1H), 7.95 (m, 1H), 8.26 (m,2H), 10.40 (s, 1H). Exact mass calculated for C₂₀H₂₀F₃N₇O₄ 479.41, found480.3 (MH⁺).

Compound B1091-{5-Nitro-6-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenylamino]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[Method 16]. yellow solid (65 mg, 84%). ¹HNMR (CDCl₃, 400 MHz) δ 1.36(t, 3H), 1.96 (m, 2H), 2.14 (m, 2H), 2.74 (m, 1H), 3.34 (m, 2H), 4.01(m, 2H), 4.26 (q, 2H), 6.02 (m, 1H), 7.14 (m, 1H), 7.47 (m, 1H), 7.56(m, 1H), 7.77 (m, 1H), 8.24 (s, 1H), 10.23 (s, 1H). Exact masscalculated for C₂₀H₂₁F₄N₅O₅ 487.40, found 488.2 (MH⁺).

Compound B110{6-[4-(4-Iodo-phenoxy)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine

Yellow solid; yield 82.6%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 10.2 (s, 1H);8.13 (s, 1H); 7.86 (m, 4H); 7.50 (m, 2H); 6.64 (m, 2H); 4.55 (m, 1H);3.65 (m, 2H); 3.55 (m, 2H); 2.98 (s, 3H); 1.96 (m, 4H). LCMS (ESI) m/z596 (M⁺H⁺, 100%).

Compound B111(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine

Following the general procedure, Compound B111 was obtained as a yellowsolid (38%). ¹H NMR 400 MHz CDCl₃ δ 10.3 (s, 1H); 8.74 (t, 1H); 8.17 (s,1H); 7.70 (d, 1H); 7.67 (d, 1H); 3.95-3.92 (m, 2H); 3.33-3.27 (m, 2H);3.29-3.23 (m, 1H); 3.00 (s, 3H); 3.03-2.96 (m, 1H); 2.19-2.11 (m, 2H);2.03-1.96 (m, 2H); 1.26 (d, 6H). Exact mass calculated for C₂₁H₂₄FN₇O₅S505.15, LCMS (ESI) m/z 506.2 (M+H⁺, 100%).

Compound B112{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine

Following the general procedure, Compound B112 was obtained as a yellowsolid (31%). ¹HNMR (CDCl₃, 400 MHz) δ 1.25 (t, 3H), 2.06-2.10 (m, 2H),2.23-2.27 (m, 2H), 2.70 (q, 2H), 2.99 (s, 3H), 3.31-3.38 (m, 3H),3.96-3.99 (m, 2H), 7.84 (dd, 4H), 8.14 (s, 1H), 10.2 (s, 1H). Exact masscalculated for C₂₀H₂₃N₇O₅S 473.1, found 474.2 (MH⁺).

Compound B113(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine

Following the general procedure, Compound B113 was obtained as a yellowsolid (44%). ¹H NMR 400 MHz CDCl₃ δ 10.2 (s, 1H); 8.13 (s, 1H); 7.87 (d,2H); 7.83 (d, 2H); 3.92 (m, 2H); 3.32-3.29 (m, 2H); 3.26-3.23 (m, 1H);2.99 (s, 3H); 2.62 (t, 2H); 2.19-2.15 (m, 2H); 2.01-1.95 (m, 2H); 1.69(se, 2H); 0.91 (t, 3H). Exact mass calculated for C₂₁H₂₅N₇O₅S 487.16,LCMS (ESI) m/z 488.2 (M+H⁺, 100%).

Compound B114{6-[4-(3-Cyclopropylmethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine

Following the general procedure, Compound B114 was obtained as a yellowsolid (45%). ¹H NMR 400 MHz CDCl₃ δ 10.2 (s, 1H); 8.15 (s, 1H); 7.87 (d,2H); 7.78 (d, 2H); 3.95 (m, 2H); 3.34-3.30 (m, 2H); 3.30-3.27 (m, 1H);3.00 (s, 3H); 2.57 (d, 2H); 2.21-2.17 (m, 2H); 2.04-1.96 (m, 2H);1.06-1.02 (m, 1H); 0.53-0.48 (m, 2H); 0.25-0.16 (m, 2H). Exact masscalculated for C₂₂H₂₅N₇O₅S 499.16, LCMS (ESI) m/z 500.5 (M+H⁺, 100%).

Compound B115{6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine

Following the general procedure, Compound B115 was obtained as a yellowsolid (76%). ¹H NMR 400 MHz CDCl₃ δ 10.2 (s, 1H); 8.14 (s, 1H); 7.85(dd, 4H); 3.92 (d, 2H); 3.27 (m, 3H); 3.0 (s, 3H); 2.14 (m, 2H); 1.99(m, 2H); 1.25 (d, 6H).

LCMS (ESI) m/z 488 (M⁺H⁺, 100%)

Compound B116{6-[4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine

Following the general procedure, Compound B116 was obtained as a yellowsolid (83.6%). ¹H NMR 400 MHz CDCl₃ δ 10.2 (s, 1H); 8.14 (s, 1H); 7.86(dd, 4H); 3.90 (d, 2H); 3.30 (m, 2H); 3.27 (m, 1H); 3.00 (s, 3H); 2.13(m, 2H); 1.98 (m, 3H); 0.97 (m, 4H). LCMS (ESI) m/z 486 (M⁺H⁺, 100%)

Compound B117(4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine

Following the general procedure, Compound B117 was obtained as a yellowsolid (61%). ¹HNMR (CDCl₃, 400 MHz) δ 2.06-2.10 (m, 2H), 2.23-2.27 (m,2H), 2.99 (s, 3H), 3.31-3.38 (m, 3H), 3.96-3.99 (m, 2H), 7.55 (t, 1H),7.70 (d, 1H), 7.86 (dd, 4H), 8.16 (s, 1H), 8.20 (d, 1H), 8.28 (s, 1H),10.2 (s, 1H). Exact mass calculated for C₂₅H₂₂F₃N₇O₅S 589.1, found 590.4(MH⁺).

Compound B1184-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfinyl-phenylamino)-pyrimidine-5-carbonitrile

Compound B99 was selectively oxidized using mCPBA to give Compound B118as the sulfoxide. ¹H-NMR (DMSO-d₆): 9.65 (1H, s), 8.26 (1H, s), 7.75(2H, m), 7.63 (2H, m), 4.52 (2H, m), 3.45 (1H, m), 3.32 (2H, m), 3.04(1H, m), 2.73 (3H, s), 2.18 (2H, m), 1.79 (2H, m) 1.18 (6H, J=7 Hz, d)ppm. LCMS: 468.4, 384.1, 356.2, 302.1.

Compound B119(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(4-trifluoromethoxy-phenoxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine

A mixture of compound(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (400mg, 1.22 mmol), 4-(4-trifluoromethoxy-phenoxy)-piperidine (399 mg, 1.34mmol) and potassium carbonate (336 mg, 2.44 mmol) in DMF (8 ml) washeated in an oil bath at 60° C. for 2 hours. The crude mixture wascooled to 0° C. and quenched with water. The solid was filtered off,rinsed with water and dried in vacuum oven to give product B119 as ayellow solid (604 mg, 90%). ¹HNMR (CDCl₃, 400 MHz) δ 2.01-2.08 (m, 4H),3.06 (s, 3H), 3.64-3.66 (m, 2H), 3.73-3.75 (m, 2H), 4.62-4.66 (m, 1H),6.93 (d, 2H), 7.17 (d, 2H), 7.93 (dd, 4H), 8.21 (s, 1H), 10.2 (s, 1H).Exact mass calculated for C₂₃H₂₂F₃N₅O₆S 553.1, found 554.3 (MH⁺).

Compound B1204-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile

Compound B99 was oxidized using mCPBA to give Compound B120 as thesulfone. ¹H NMR (DMSO-d₆): 9.86 (1H, s), 8.34 (1H, s), 7.93˜7.84 (4H,m), 4.54 (2H, m), 3.50˜3.39 (3H, m), 3.21 (3H, s) 3.05 (1H, m), 2.21(2H, m), 1.83 (2H, m) 1.27 (6H, J=7 Hz, d) ppm. LCMS: 452.1, 437.2,368.1, 340.0.

Compound B1211-{1-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one

The general procedure for the addition of Amine to pyrimidine affordedCompound 121; ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 10.48 (s, NH); 8.84 (s,1H); 8.23 (s, 1H); 7.75 (m, 2H); 3.98 (m, 2H); 3.22 (m, 2H); 3.06 (s,CH₃); 2.69 (m, 1H); 2.48 (m, 2H); 1.99 (m, 2H); 1.77 (m, 2H), 1.59 (m,2H), 1.29 (m, 4H), 0.89 (1, 3H); LCMS (ESI) for C₂₂H₂₈FN₅O₅S: m/z 493(M+H⁺, 100%).

Compound B1221-{1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one

The general procedure for the addition of Amine to pyrimidine affordedCompound 122; ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 10.2 (s, NH); 8.20 (s,1H); 7.92 (m, 4H); 3.98 (m, 2H); 3.22 (m, 2H); 3.06 (s, CH₃); 2.69 (m,1H); 2.48 (m, 2H); 1.99 (m, 2H); 1.77 (m, 2H), 1.59 (m, 2H), 1.29 (m,4H), 0.89 (t, 3H); LCMS (ESI) for C₂₂H₂₉N₅O₅S: m/z 476 (M+H⁺, 100%).

Compound B123{6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine

The general procedure for the addition of Amine to pyrimidine affordedCompound B123 as yellow oil (40 mg, 51%). ¹H NMR 400 MHz CDCl₃ d(ppm):10.4 (s, NH); 8.83 (t, 1H); 8.25 (s, 1H); 7.76 (t, 2H); 4.01 (d, 2H);3.41-3.34 (m, 2H); 3.32-3.28 (m, 1H); 3.08 (s, 3H); 2.27-2.22 (m, 2H);2.11-2.04 (m, 2H); 3.36 (s, 9H). Exact mass calculated for:

C₂₃H₂₇FN₆O₅S 518.17, LCMS (ESI) m/z 520.4 (M+H⁺, 100%).

Compound B124{6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine

The general procedure for the addition of amine to pyrimidine affordedCompound 124 as a yellow solid, yield 90%; ¹H NMR 400 MHz CDCl₃ δ (ppm):10.2 (s, 1H); 8.23 (s, 1H); 7.97 (d, 2H); 7.76 (d, 2H); 4.02 (d, 2H);3.44 (m, 3H); 3.2 (s, 3H); 2.27 (m, 2H); 2.03 (m, 2H); 1.37 (s, 9H);LCMS (ESI) m/z 502 (M⁺H⁺, 100%)

Compound B125[6-(4-Benzofuran-2-yl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine

The general procedure for the addition of amine to pyrimidine affordedCompound B125 as a yellow solid (82 mg, 91%). ¹H NMR (CDCl₃, 400 MHz) δ1.00 (s, 1H), 1.54 (m, 2H), 1.93 (m, 2H), 2.97 (s, 3H), 3.09 (m, 2H),3.74 (m, 2H), 6.42 (s, 1H), 6.98 (m, 3H), 7.27 (d, 1H), 7.32 (d, 1H),7.66 (m, 4H), 7.97 (s, 1H). Exact mass calculated for C₂₀H₂₁F₂N₅O₃493.53, found 494.4 (M+H⁺).

Compound B1264-(3-Fluoro-4-methanesulfonyl-phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile

Compound B126 was obtained as a solid (90%). ¹HNMR (CDCl₃, 400 MHz) δ1.34 (d, 6H), 2.01-2.08 (m, 2H), 2.23-2.27 (m, 2H), 3.06 (heptet, 1H),3.22 (s, 3H), 3.30-3.34 (m, 1H), 3.46-3.50 (m, 2H), 4.70-4.77 (m, 2H),7.33 (dd, 1H), 7.40 (s, 1H), 7.90 (t, 1H), 8.08 (dd, 1H), 8.38 (s, 1H).Exact mass calculated for C₂₂H₂₄FN₇O₃S 485.2, found 486.3 (MH⁺).

Compound B127{6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(5-methanesulfonyl-pyridin-2-yl)-amine

Compound B127 was prepared by the general procedure for the addition ofpyridinylsulfone to pyrimidine to give a solid (4 mg, 4%). ¹H NMR 400MHz CDCl₃ δ(ppm): 10.5 (s, NH); 8.86 (s, 1H); 8.74 (d, 1H); 8.29 (s,1H); 8.20 (d, 1H); 4.02-3.99 (m, 2H); 3.40-3.28 (m, 3H); 3.11 (s, 3H);3.11-3.06 (m, 1H); 2.26-2.22 (m, 2H); 2.09-2.03 (m, 2H); 1.33 (d, 6H).Exact mass calculated for C₂₀H₂₄N₈O₅S 488.16, LCMS (ESI) m/z 489.3(M+H⁺, 100%).

Compound B128(3-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine

Compound B128 was prepared using the general procedure for the oxidationof a sulfide to sulfone; yellow solid (9 mg, 36%). ¹H NMR 400 MHz CDCl₃δ(ppm): 10.3 (s, NH); 8.25 (s, 1H); 8.13 (d, 1H); 7.92 (t, 1H); 7.40 (d,1H); 4.00 (db, 2H); 3.41-3.29 (m, 3H); 3.23 (s, 3H); 3.10-3.07 (m, 1H);2.26-2.24 (m, 2H); 2.10-2.02 (m, 2H); 1.34 (d, 6H). Exact masscalculated for C₂₁H₂₄FN₇O₅S 505.15, LCMS (ESI) m/z 506.3 (M+H⁺, 100%).

Compound B129{6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(6-methanesulfonyl-pyridin-3-yl)-amine

Compound B129 was prepared using the general procedure for the oxidationof a sulfide to sulfone; yellow solid (6 mg, 67%). ¹H NMR 400 MHz CDCl₃δ(ppm): 10.3 (s, NH); 8.93 (s, 1H); 8.52 (d, 1H); 8.22 (s, 1H); 8.10 (d,1H); 4.00 (db, 2H); 3.41-3.31 (m, 3H); 3.23 (s, 3H); 3.08 (qu, 1H);2.27-2.23 (m, 2H); 2.10-2.04 (m, 2H); 1.33 (d, 6H). Exact masscalculated for C₂₀H₂₄N₈O₅S 488.16, LCMS (ESI) m/z 489.2 (M+H⁺, 100%).

Compound B1304-(2,3-Difluoro-phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile

To a solution of 4,6-dichloro-pyrimidine-5-carbonitrile (254 mg, 1.47mmol) and 2,3-difluoroaniline (190 mg, 1.47 mmol) in DMF (3 mL) at 0° C.was added K₂CO₃ (203 mg, 1.47 mmol). The completion of the reaction wasmonitored by TLC (EtOAc:Hex 1:1, R_(f)=0.90). After the completion ofthe reaction, 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (340 mg,1.47 mmol) and K₂CO₃ (406 mg, 2.94 mmol) were added at 0° C. Thereaction was warmed to rt and stirred for 30 min. The reaction washeated to 40° C. and maintained for 1 h. The reaction was cooled to rt,poured in to H₂O (50 mL) and extracted with EtOAc (50 mL, two times).The EtOAc was dried over MgSO₂ and concentrated under vacuum. The crudeproduct was purified over SiO₂ (EtOAc:Hex=1:1, R_(f)=0.49) to affordCompound B130 (501 mg; 76.7%). ¹H-NMR (DMSO-d₆): 9.60 (1H, s), 8.28 (1H,s), 7.45-7.29 (3H, m), 4.64 (2H, m), 3.59-3.52 (4H, m), 3.41-3.49 (2H,m), 2.29-2.25 (2H, b), 1.96-1.86 (2H, m), 1.39 (6H, d) ppm. LCMS:426.43.

Compound B1314-(2,5-Difluoro-phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile

To a solution of 4,6-Dichloro-pyrimidine-5-carbonitrile (254 mg, 1.47mmol) and 2,5-difluoroaniline (190 mg, 1.47 mmol) in DMF (3 mL) at 0° C.was added K₂CO₃ (203 mg, 1.47 mmol). The completion of the reaction wasmonitored by TLC (EtOAc:Hex=1:1, R_(f)=0.90). After the reaction wascomplete, 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (340 mg, 1.47mmol) and K₂CO₃ (406 mg, 2.94 mmol) were added at 0° C. The reaction waswarmed to rt and stirred for 30 min. The reaction was heated to 40° C.and maintained for 1 h. The reaction was cooled to rt, poured in to H₂O(50 mL) and extracted with EtOAc (50 mL, two times). The EtOAc was driedover MgSO₂ and concentrated under vacuum. The crude product was purifiedover SiO₂ (EtOAc:Hex=1:1, R_(f)=0.44) to afford the desired CompoundB131 (465 mg; 71.1%). ¹H-NMR (DMSO-d₆): 9.32 (1H, s), 8.19 (1H, s),7.40˜7.08 (3H, m), 4.54 (2H, m), 3.48˜3.32 (4H, m), 3.07˜3.01 (2H, m),2.18˜2.14 (2H, b), 1.96˜1.86 (2H, m), 1.27 (6H, d) ppm. LCMS: 426.43.

Compound B1324-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile

Compound B132 was prepared by the general procedure for the addition ofamine to pyrimidine as described herein using4-chloro-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile and4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine. ¹H-NMR (DMSO-d6): 9.38(1H, s), 8.21 (1H, s), 7.47 (2H, J=4.3 Hz, d), 7.23 (2H, J=4.3 Hz, d),4.50 (2H, m), 3.35 (2H, m), 3.02 (1H, m), 2.51 (3H, s), 2.18 (2H, m),1.79 (2H, m) 1.83 (6H, J=7 Hz, d) ppm. LCMS: 436.3, 351.9, 324.4, 270.2.

Intermediate4-chloro-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile wasprepared in a similar manner as described herein using4,6-dichloro-pyrimidine-5-carbonitrile and 4-methylsulfanyl-phenylamine.¹H-NMR (DMSO-d6): 10.22 (1H, s), 8.53 (1H, s) 7.43 (2H, m), 7.40 (2H,m), 2.49 (3H, s) ppm. LCMS: 277.0, 234.0, 149.0.

Compound B1334-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile

To a solution of4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile(200 mg, 0.46 mmol) in dichloromethane (5 mL) at 0° C. was added 216 mgof m-CPBA (0.94 mmol). The reaction was stirred for 10 min and warmed toroom temperature. The reaction was maintained for 2 h at the sametemperature and the completion of the reaction was judged by TLC. Thereaction was concentrated under vacuum and purified over SiO₂ (ethylacetate/Hex=1/1 m R_(f)=0.69) to afford Compound B133 (167 mg, 80%).¹H-NMR (DMSO-d6): 9.86 (1H, s), 8.34 (1H, s), 7.93˜7.84 (4H, m), 4.54(2H, m), 3.50˜3.39 (3H, m), 3.21 (3H, s) 3.05 (1H, m), 2.21 (2H, m),1.83 (2H, m) 1.27 (6H, J=7 Hz, d) ppm. LCMS: 452.1, 437.2, 368.1, 340.0.

Compound B1344-(4-Hexanoyl-piperidin-1-yl)-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile

4-Chloro-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile(150.00 mg, 0.54 mmol) in DMF (2 ml) was mixture with PotassiumCarbonate (82.1 mg, 0.59 mmol), added 1-piperidin-4-yl-hexan-1-onehydrochloride (237.4 mg, 1.08 mmol) in DMF (1 ml) and left stirring atroom temperature for 1 hour. Reaction was worked up with ethyl acetate,sodium bicarbonate, dried with magnesium sulfate, filtered andconcentrate under high vacuum to afford a lithe yellow solid as product.Compound was recrystallized using hexane in ethyl acetate to affordCompound B134 (157 mg). LCMS (ESI) for C₂₂H₂₈N₆OS: m/z 425.4 (M+H⁺,100%). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.72 (d, 1H), 8.40 (s, 1H), 7.97(q, 1H), 7.21 (s, 1H, NH), 4.92 (m, 2H), 3.42 (m, 2H), 2.86 (m, 1H),2.75 (s, 3H), 2.65 (t, 2H), 2.15 (m, 2H), 1.77 (m, 2H), 1.50 (m, 2H),1.50 (m, 2H), 1.07 (t, 3H).

Compound B1354-(4-Hexanoyl-piperidin-1-yl)-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile

4-(4-Hexanoyl-piperidin-1-yl)-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile(100 mg, 0.236 mmol) in chloroform was mixture with mCPBA (122.0 mg,0.71 mmol) at 0 C under stirring, left reaction warmed up to roomtemperature and reacted for an additional 12 hours. Worked up with water(pH=10 using ammonium hydroxide as base), chloroform, sodiumbicarbonate, dried with magnesium sulfate, concentrate under high vacuumand crystallized using hexane and ethyl acetate to afford Compound B135as a solid (90 mg, 84%). LCMS (ESI) for C₂₂H₂₈N₆O₃S: m/z 457.2 (M+H⁺,100%). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.87 (d, 1H), 8.46 (q, 1H), 8.32(s, 1H), 8.07 (d, 1H), 7.42 (s, 1H, NH), 4.74 (m, 2H), 3.48 (m, 2H),3.21 (s, 3H), 2.70 (m, 1H), 2.48 (t, 2H), 1.98 (m, 2H), 1.58 (m, 2H),1.27 (m, 2H), 1.27 (m, 2H), 0.89 (t, 3H).

Compound B1364-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile

4-Chloro-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile(80.00 mg, 0.29 mmol) in DMF (2 ml) was mixture with Potassium Carbonate(79.62 mg, 0.58 mmol), added4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (237.4mg, 1.08 or 1.02 mmol) in DMF (1 ml) and left stirring at roomtemperature for 1 hour. Reaction was worked up with ethyl acetate,sodium bicarbonate, dried with magnesium sulfate, filtered andconcentrate under high vacuum. Compound was recrystallized using hexanein ethyl acetate to afford Compound B136. ¹H NMR 400 MHz DMSO δ (ppm):9.48 (s, 1H), 8.55 (d, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.77 (d, 1H),7.26 (d, 1H), 4.52 (m, 2H), 3.48 (m, 1H), 3.37 (m, 2H), 3.32 (s, 3H),3.04 (m, 1H), 2.14 (m, 2H), 1.75 (m, 2H), 1.33 (d, 6H).

Compound B1374-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile

4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile(26.0 mg, 0.06 mmol) in chloroform was mixture with mCPBA (41.1 mg, 0.24mmol) at 0 C under stirring, left reaction warmed up to room temperatureand reacted for an additional 12 hours. Worked up with water (pH=10using ammonium hydroxide as base), chloroform, sodium bicarbonate, driedwith magnesium sulfate, concentrate under high vacuum and crystallizedusing hexane and ethyl acetate to afford Compound B137 as a solid (7.5mg). ¹H NMR 400 MHz DMSO δ (ppm): 8.88 (d, 1H), 8.55 (d, 1H), 8.35 (s,1H), 8.08 (d, 1H), 7.44 (s, 1H), 4.72 (m, 2H), 3.48 (m, 1H), 3.30 (m,1H), 3.22 (s, 3H), 3.08 (m, 1H), 2.23 (m, 2H), 2.03 (m, 2H), 1.33 (d,6H).

Compound B1381-[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidin-5-yl]-ethanone

To a solution of1-[4-Chloro-6-(4-methanesulfonyl-phenylamino)-pyrimidin-5-yl]-ethanone(0.21 mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidinehydrochloride (0.21 mmol, 49 mg) in N,N-dimethyl formamide (500 uL) wasadded potassium carbonate (0.21 mmol, 29 mg). The resulting mixture wasmicrowaved at 100° C. for 150 seconds. Its progress was monitored bythin layer chromatography and LCMS. The reaction was treated with waterand the desired compound was extracted in ethyl acetate. Organic layerwas evaporated in vacuo. Purification by HPLC provided Compound B138 asa white solid (15 mg, 15%). ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 10.85 (s,1H); 8.32 (s, 1H); 7.92 (s, 4H); 4.07 (m, 2H); 3.40 (m, 2H); 3.29 (h,1H); 3.09 (m, 1H); 3.07 (s, 3H); 2.47 (s, 3H); 2.18 (m, 2H); 2.03 (m,2H), 1.33 (d, 6H). LCMS (ESI), m/z 485.3 (M+H+, 100%).

Compound B1391-[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone

To a solution of1-[4-chloro-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone(0.21 mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidinehydrochloride (0.21 mmol, 49 mg) in N,N-dimethyl formamide (500 uL) wasadded potassium carbonate (0.21 mmol, 29 mg). The mixture was microwavedat 100° C. for 150 seconds. Its progress was monitored by thin layerchromatography and LCMS. The reaction was treated with water and thedesired compound was extracted in ethyl acetate. Organic layer wasevaporated in vacuo. Purification by HPLC provided Compound B139 as awhite solid (31 mg, 31%). ¹H-NMR (400 MHz, CDCl₂) δ(ppm): 10.9 (s, 1H);8.90 (d, 1H); 8.58 (d, 1H); 8.32 (s, 1H); 8.05 (d, 1H); 4.09 (m, 2H);3.41 (m, 2H); 3.29 (h, 1H); 3.23 (s, 3H); 3.09 (h, 1H); 2.48 (s, 3H),2.18 (m, 2H), 2.02 (m, 2H), 1.35 (d, 6H) LCMS (ESI), m/z 486.3 (M+H+,100%).

Example 14 Syntheses of Compounds of the Present Invention Compound C11-(5-Nitro-6-phenyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethylester

General Method 17. A mixture of1-(6-chloro-5-nitropyrimidine-4-yl)-piperidine-4-carboxylic acid ethylester (0.157 g, 0.49 mmol), phenyl boronic acid (62.1 mg, 0.50 mmol),tetrakistriphenylphosphinepalladium(0) (11.6 mg), 2M Na₂CO₃ (375 μL),DME/H₂O/ethanol (7/3/2) (1239 μL) was heated in a microwave tube at 140°C. for 120 s in a microwave reactor. The reaction mixture was cooled andfiltered and the filtrate was partitioned between ethyl acetate andwater. The organic layer was washed with 1N NaOH (2×) and brine, dried(Na₂CO₃) and evaporated. Flash column chromatography (Biotage, silica,20% EtOAc/hexane) afforded the desired product C1 in 47% yield. ¹H NMR,400 MHz, CDCl₃, δ (ppm): 8.63 (s, 1H); 7.45 (m, 5H); 4.16 (q, 2H); 4.07(m, 2H); 3.20 (t, 2H); 2.62 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.28(t, 3H). LCMS (ESI) for C₁₈H₂₀N₄O₄: m/z 356 (M+H⁺, 100%)

Compound C21-(6-Naphthalen-2-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by HPLC afforded the pureproduct. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.62 (s, 1H); 7.93 (s, 1H);7.80 (m, 3H); 7.50 (m, 3H); 4.10 (q, 2H); 3.99 (m, 2H); 3.16 (t, 2H);2.58 (m, 1H); 1.98 (m, 2H); 1.21 (t, 3H). LCMS (ESI) for C₂₂H₂₂N₄O₄: m/z406 (M+H⁺, 100%)

Compound C31-[6-(4-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by preparatory LCMSafforded the pure product in 7%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.66(s, 1H); 8.02 (d, 1H); 7.66 (d, 1H); 4.18 (q, 2H); 4.05 (m, 2H); 3.27(t, 2H); 3.09 (s, 3H); 2.66 (m, 1H); 2.06 (m, 2H); 1.88 (m, 2H); 1.28(t, 3H). LCMS (ESI) for C₁₉H₂₂N₄O₆S: m/z 434 (M+H⁺, 100%)

Compound C41-(6-Benzofuran-5-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester

[method 17]. Flash column chromatography (Biotage, silica, 20%EtOAc/hexane) afforded the product in 61% yield. ¹H NMR, 400 MHz, CDCl₃,δ (ppm): 8.63 (s, 1H); 7.66 (d, 1H); 7.57 (s, 1H); 7.54 (d, 1H); 7.39(t, 1H); 7.28 (t, 1H); 4.15 (m, 4H); 3.22 (1, 2H); 2.63 (m, 1H); 2.04(m, 2H); 1.85 (m, 2H); 1.28 (t, 3H). LCMS (ESI) for C₂₂H₂₀N₄O₅: m/z 396(M+H⁺, 100%)

Compound C51-[5-Nitro-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by HPLC afforded the pureproduct in 11%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.65 (s, 1H); 7.46 (q,1H); 4.18 (q, 2H); 4.05 (m, 2H); 3.24 (m, 3H); 2.65 (m, 1H); 2.05 (m,2H); 1.86 (m, 2H); 1.27 (t, 3H). LCMS (ESI) for C₁₉H₂₂N₄O₄: m/z 370(M+H⁺, 100%)

Compound C61-[6-(4-Methoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Flash column chromatography (Biotage, silica, 20%EtOAc/hexane) afforded the product in 24% yield. ¹H NMR, 400 MHz, CDCl₃,δ (ppm): 8.60 (s, 1H); 7.47 (d, 1H); 6.94 (, 2H); 4.15 (q, 2H); 4.03 (m,2H); 3.84 (s, 2H); 3.17 (m, 2H); 2.61 (m, 1H); 1.96 (m, 2H); 1.83 (m,2H); 1.27 (t, 3H). LCMS (ESI) for C₁₉H₂₂N₄O₃: m/z 386 (M+H⁺, 100%)

Compound C7 4-(4-Butyl-piperidin-1-yl)-6-furan-3-yl-5-nitro-pyrimidine

[method 17]. Flash column chromatography (Biotage, silica, 20%EtOAc/hexane) afforded the product in 35% yield. ¹H NMR, 400 MHz, CDCl₃,δ (ppm): 8.55 (s, 1H); 7.97 (s, 1H); 7.46 (s, 1H); 6.73 (s, 2H); 4.16(q, 2H); 3.18 (m, 2H); 2.61 (m, 1H); 2.01 (m, 2H); 1.83 (m, 2H); 1.27(t, 3H). LCMS (ESI) for C16H₁₈N₄O₅: m/z 346 (M+H⁺, 100%)

Compound C81-[6-(3-Chloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by HPLC afforded the pureproduct in 14%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.67 (s, 1H); 7.47 (m,1H); 7.38 (t, 1H); 7.32 (m, 1H); 4.18 (q, 2H); 4.05 (m, 2H); 3.28 (t,2H); 2.67 (m, 1H); 2.07 (m, 2H); 1.88 (m, 2H); 1.28 (t, 3H). LCMS (ESI)for C₁₈H₁₉ClN₄O₄; m/z 390 (M+H⁺, 100%)

Compound C91-[6-(2,6-Dimethoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by HPLC afforded the pureproduct in 28%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.79 (s, 1H); 7.95 (s,3H); 7.40 (t, 1H); 6.59 (d, 2H); 4.18 (q, 2H); 4.07 (m, 2H); 3.74 (s,6H); 3.38 (t, 2H); 2.70 (m, 1H); 2.10 (m, 2H); 1.95 (m, 2H); 1.28 (t,3H). LCMS (ESI) for C₁₈H₁₉ClN₄O₄: m/z 390 (M+H⁺, 100%)

Compound C101-(6-Naphthalen-1-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester

[method 17]. The reaction mixture was filtered through Celite andactivated carbon and purified by preparatory LCMS. ¹H NMR 400 MHz CDCl₃δ□(ppm): 8.75 (s, 1H); 7.96 (m, 1H); 7.90 (m, 2H); 7.51 (m, 3H); 7.40(m, 1H); 4.19 (m, 2H); 4.11 (m, 2H); 3.31 (m, 2H); 2.68 (m, 1H); 2.08(m, 2H); 1.91 (m, 2H); 1.29 (m, 3H). LCMS (ESI) m/z 407 (M+H⁺, 100%)

Compound C111-[6-(4-Methylsulfanyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. The reaction mixture was filtered through Celite andactivated carbon and purified by preparatory LCMS. ¹H NMR. 400 MHz CDCl₃δ□(ppm); 8.68 (s, 1H); 7.41 (m, 2H); 7.28 (m, 2H); 4.18 (m, 2H); 4.07(m, 2H); 3.27 (m, 2H); 2.66 (m, 1H); 2.52 (s, 3H); 2.03 (m, 2H); 1.85(m, 2H); 1.29 (m, 3H). LCMS (ESI) m/z 403 (M+H⁺, 100%)

Compound C121-(2′,4′-Dihydroxy-5-nitro-[4,5′]bipyrimidinyl-6-yl)-piperidine-4-carboxylicacid ethyl ester

[method 17]. The reaction mixture was filtered through Celite andactivated carbon and purified by HPLC w/TFA. Yield 0.015 g, 11%. Yellowsolid. ¹H NMR 400 MHz CDCl₃□□(ppm): 8.48, 7.33 (s, 1H); 8.02 (s, 1H);4.07 (m, 2H); 3.86 (m, 2H); 3.13 (m, 2H); 2.65 (s, 2H); 2.55 (m, 1H);1.93 (m, 2H); 1.74 (m, 2H); 1.18 (m, 3H). LCMS (ESI) m/z 391 (M+H⁺,100%)

Compound C131-[6-(4-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17] Yield: 6 mg (4%). ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.66 (s,1H); 8.02 (d, 1H); 7.66 (d, 1H); 4.18 (q, 2H); 4.05 (m, 2H); 3.27 (t,2H); 3.09 (s, 3H); 2.66 (m, 1H); 2.06 (m, 2H); 1.88 (m, 2H); 1.28 (t,3H). LCMS (ESI) for C₁₉H₂₂N₄O₆S: m/z 434 (M+H⁺, 100%)

Compound C141-[6-(3,5-Bis-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by preparatory LCMSafforded the pure product in 23%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.64(s, 1H); 7.96 (s, 3H); 4.18 (q, 2H); 4.05 (m, 2H); 3.25 (1, 2H); 2.65(m, 1H); 2.05 (m, 2H); 1.85 (m, 4H); 1.28 (t, 3H). LCMS (ESI) forC₂₀H₁₈F₆N₄O₄: m/z 492 (M+H⁺, 100%)

Compound C151-(6-Dibenzothiophen-4-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by preparatory LCMSafforded the pure product in 24%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.72(s, 1H); 8.20 (d, 1H); 8.12 (m, 1H); 7.76 (m, 1H); 7.45 (m, 4H); 7.37(m, 1H); 4.14 (q, 2H); 4.05 (m, 2H); 3.27 (t, 2H); 2.64 (m, 1H); 2.03(m, 2H); 1.86 (m, 2H); 1.25 (t, 3H). LCMS (ESI) for C₂₄H₂₂N₄O₄S: m/z 462(M+H⁺, 100%)

Compound C161-[6-(3,5-Dimethyl-isoxazol-4-yl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by preparatory LCMSafforded the pure product in 12%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.64(s, 1H); 4.18 (q, 2H); 4.05 (m, 2H); 3.25 (t, 2H); 2.66 (m, 1H); 2.35(s, 3H); 2.21 (s, 3H); 2.05 (m, 2H); 1.86 (m, 2H); 1.28 (t, 3H). LCMS(ESI) for C₁₇H₂₁N₅O₅: m/z 375 (M+H⁺, 100%)

Compound C171-(5-Nitro-6-thiophen-2-yl-pyrimidin-4-yl)-piperidine-4-carboxylic acidethyl ester

[method 17]. Purification of the crude product by preparatory LCMSafforded the pure product in 23%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.56(s, 1H); 7.58 (d, 1H); 7.47 (d, 1H); 7.10 (t, 1H); 4.17 (q, 2H); 4.09(d, 2H); 3.21 (t, 2H); 2.62 (m, 1H); 2.03 (m, 2H); 1.85 (m, 2H); 1.28(t, 3H). LCMS (ESI) for C₁₆H₁₈N₄O₄S: m/z 362 (M+H⁺, 100%)

Compound C181-[6-(3,5-Dichloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by preparatory LCMSafforded the pure product in 7%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.59(s, 1H); 7.44 (s, 1H); 7.30 (s, 2H); 7.23 (s, 1H); 4.14 (q, 2H); 4.00(m, 2H); 3.21 (m, 2H); 2.61 (m, 1H); 2.02 (m, 2H); 1.81 (m, 2H); 1.25(t, 3H). LCMS (ESI) for C₁₆H₁₈N₄O₄S: m/z 362 (M+H⁺, 100%)

Compound C191-(6-Dibenzofuran-4-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by preparatory LCMSafforded the pure product in 17%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.77(s, 1H); 8.07 (d, 1H); 7.96 (d, 1H); 7.45 (m, 4H); 7.36 (t, 1H); 4.18(q, 2H); 4.08 (m, 2H); 3.31 (t, 2H); 2.69 (m, 1H); 2.07 (m, 2H); 1.92(m, 2H); 1.29 (t, 3H). LCMS (ESI) for C₂₄H₂₂N₄O₅: m/z 446 (M+H⁺, 100%)

Compound C201-[6-(3,5-Dimethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by preparatory LCMSafforded the pure product in 23%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.46(s, 1H); 6.93 (s, 3H); 4.02 (q, 2H); 3.89 (m, 2H); 3.05 (m, 2H); 2.47(m, 1H); 2.20 (s, 6H); 1.88 (m, 2H); 1.70 (m, 4H); 1.18 (t, 3H). LCMS(ESI) for C₁₈H₁₈ClN₄O₄: m/z 384 (M+H⁺, 100%)

Compound C211-[6-(4-Acetyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

Filtered the reaction mixture and the filtrate was purified by semipreparatory HPLC afforded the pure product in 21%. ¹H NMR, 400 MHz,CDCl₃, δ (ppm): 8.63 (s, 1H); 8.00 (d, 2H); 7.57 (d, 2H); 4.16 (q, 2H);4.03 (m, 2H); 3.22 (m, 2H); 2.64 (s, 3H); 2.03 (m, 2H); 1.85 (m, 4H);1.27 (t, 3H). LCMS (ESI) for C₂₀H₂₂N₄O₅: m/z 398 (M+H⁺, 100%)

Compound C221-[6-(4-Ethanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by preparatory TLC using20% EtOAc/hexane afforded the pure product in 21%. ¹H NMR, 400 MHz,CDCl₃, δ (ppm): 8.63 (s, 1H); 7.97 (d, 2H); 7.67 (d, 2H); 4.18 (q, 2H);3.22 (m, 2H); 3.12 (m, 3H); 2.65 (m, 1H); 2.04 (m, 2H); 1.85 (m, 2H);1.28 (t, 3H). LCMS (ESI) for C₂₀H₂₄N₄O₆S: m/z 448 (M+H⁺, 100%)

Compound C231-[6-(2-Fluoro-biphenyl-4-yl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. purified by semi preparatory HPLC afforded the pure productin 14%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.54 (s, 1H); 7.35 (m, 8H);4.07 (q, 2H); 3.96 (m, 2H); 3.13 (t, 2H); 2.53 (m, 1H); 1.95 (m, 2H);1.77 (m, 2H); 1.19 (t, 3H). LCMS (ESI) for C₂₀H₂₂N₄O₅: m/z 398 (M+H⁺,100%)

Compound C241-[6-(3-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the crude product by flash columnchromatography (Biotage, silica, 20% EtOAc/hexane) afforded the pureproduct in 5%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.67 (s, 1H); 8.07 (m,2H); 7.69 (m, 2H); 4.18 (q, 2H); 4.09 (m, 2H); 3.29 (t, 2H); 3.08 (s,3H); 2.71 (m, 1H); 2.06 (m, 2H); 1.87 (m, 2H); 1.27 (t, 3H). LCMS (ESI)for C₁₉H₂₂N₄O₆S: m/z 434 (M+H⁺, 100%)

Compound C251-{6-[4-(2-Carboxy-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 17]. C25 was purified by preparatory HPLC afforded the pureproduct in 24%. ¹H NMR, 400 MHz, CDCl₃, δ (ppm): 8.52 (s, 1H); 7.33 (d,2H); 7.17 (d, 2H); 4.07 (m, 2H); 3.94 (m, 2H); 3.10 (t, 2H); 2.94 (t,2H); 2.64 (t, 2H); 2.52 (m, 1H); 1.40 (t, 3H). LCMS (ESI) forC₂₁H₂₄N₄O₆: m/z 428 (M+H⁺, 100%)

Compound C261-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid methyl ester

[method 17]. Purification of the residue by column chromatography(silica, 20% EtOAc/hexane) afforded the pure product in 14%. ¹H NMR, 400MHz, CDCl₃, δ (ppm): 8.55 (s, 1H); 7.36 (d, 2H); 7.19 (d, 2H); 3.95 (m,2H); 3.64 (s, 3H); 3.60 (s, 3H); 3.11 (m, 2H); 2.92 (t, 2H); 2.57 (t,2H); 2.54 (m, 1H); 1.95 (m, 2H); 1.76 (m, 2H). LCMS (ESI) forC₂₁H₂₄N₄O₆: m/z 428 (M+H⁺, 100%).

Compound C271-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester

[method 17]. Purification of the residue by preparatory TLC (silica, 20%EtOAc/hexane) afforded the pure product in 16%. ¹H NMR, 400 MHz, CDCl₃,δ (ppm): 8.55 (s, 1H); 7.35 (d, 2H); 7.19 (d, 2H); 4.09 (q, 2H); 3.96(m, 2H); 3.60 (s, 3H); 3.11 (m, 2H); 2.92 (t, 2H); 2.57 (t, 2H); 1.94(s, 3H); 1.77 (m, 2H); 1.19 (t, 3H). LCMS (ESI) for C₂₂H₂₆N₄O₆: m/z 442(M+H⁺, 100%).

Example 15 Syntheses of Compounds of the Present Invention Compound D11-[5-Nitro-6-(2-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester. General Method 18

1-{6-chloro-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethylester (100 mg, 0.317 mmol), Pd(PPh₃)₂Cl₂ (12 mg, 0.017 mmol) andcopper(I)iodide (5 mg, 0.026 mmol) were dissolved indiisopropylethylamine and stirred for 2 min.o-ethynyl-trifluoromethylbenzene (100 ul, 0.072 mmol) was added and themixture stirred under N₂ at 70° C. for 18 hours. The yellow suspensionturned black. After cooling to room temperature, the reaction mixturewas diluted with chloroform (12 ml), passed through a celite plug andconcentrated under vacuo. Purification by Flash Chromatography (0-30%Ethyl acetate/Hexanes) gave Compound D1. Yield 35%. ¹H NMR 400 MHz CDCl₃δ (ppm): 8.58 (s, 1H); 7.78 (d, 1H); 7.71 (d, 1H); 7.56 (m, 2H); 4.16(m, 2H); 4.01 (d, 2H); 3.21 (m, 2H); 2.63 (m, 1H); 2.03 (m, 2H); 1.84(m, 2H); 1.26 (t, 3H). LCMS (ESI) m/z 449 (M⁺H⁺, 100%)

Compound D21-(5-Nitro-6-phenylethynyl-pyrimidin-4-yl)-piperidine-4-carboxylic acidethyl ester

[method 18]. Purification by HPLC yielded red oil. Yield 9%. ¹H NMR 400MHz CDCl₃ δ (ppm): 8.49 (s, 1H); 7.54 (d, 2H); 7.32 (d, 3H); 4.11 (m,2H); 3.95 (d, 2H); 3.20 (m, 2H); 2.58 (m, 1H); 2.01 (m, 2H); 1.80 (m,2H); 1.21 (t, 3H). LCMS (ESI) m/z 381 (M+H⁺, 100%)

Compound D31-[5-Nitro-6-(4-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 18]. Purification by HPLC. Yield 30% brown solid. ¹H NMR 400 MHzCDCl₃ δ (ppm): 8.55 (s, 1H); 7.7 (d, 2H); 7.65 (d, 2H); 4.17 (m, 2H);4.00 (d, 2H); 3.24 (m, 2H); 2.64 (m, 1H); 1.96 (m, 4H); 1.28 (t, 3H).LCMS (ESI) m/z 449 (M+H⁺, 100%)

Compound D41-(5-Nitro-6-m-tolylethynyl-pyrimidin-4-yl)-piperidine-4-carboxylic acidethyl ester

Purification by HPLC. Yield 60% brown solid. ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.55 (s, 1H); 7.44 (d, 2H); 7.27 (d, 2H); 4.18 (m, 2H); 4.00 (d,2H); 3.24 (m, 2H); 2.64 (m, 1H); 2.37 (s, 3H); 2.04 (m, 2H); 1.87 (m,2H); 1.28 (t, 3H). LCMS (ESI) m/z 395 (M+H⁺, 100%)

Compound D51-[6-(2-Fluoro-phenylethynyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

¹H NMR 400 MHz CDCl₃ δ (ppm): 8.58 (s, 1H); 7.78 (d, 1H); 7.71 (d, 1H);7.56 (m, 2H); 4.16 (m, 2H); 4.01 (d, 2H); 3.21 (m, 2H); 2.63 (m, 1H);2.03 (m, 2H); 1.84 (m, 2H); 1.26 (t, 3H). LCMS (ESI) m/z 449 (M+H⁺,100%)

Compound D61-[5-Nitro-6-(3-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester

[method 18]. Purification by Flash Chromatography (20-30% Ethylacetate/Hexanes). Yield 42%. ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.55 (s, 1H);7.87 (s, 1H); 7.78 (d, 1H); 7.68 (d, 1H); 7.55 (m, 1H); 4.19 (m, 2H);4.00 (d, 2H); 3.23 (m, 2H); 2.65 (m, 1H); 2.04 (m, 2H); 1.86 (m, 2H);1.27 (t, 3H). LCMS (ESI) m/z 449 (M⁺H⁺, 100%)

Example 16 Syntheses of Compounds of the Present Invention5-Nitro-4-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidineCompound E1

[Method 16]. yellow solid (56 mg, 80%). ¹HNMR (CDCl₃, 400 MHz) δ 1.61(m, 2H), 2.02 (m, 2H), 3.22 (m, 2H), 3.69 (m, 2H), 3.98 (m, 2H), 6.87(m, 1H), 6.94 (m, 1H), 7.30 (m, 4H), 7.72 (m, 2H), 7.89 (m, 1H), 8.20(m, 1H). Exact mass calculated for C₂₂H₁₉N₇O₃S₂ 493.56, found 494.5(MH⁺).

The compounds in the above examples were screened in the MembraneCyclase Assay. Representative compounds are shown in the table below:

RUP3 (IC₅₀) Compound Membrane Cyclase (μM) A124 0.241 B70 0.129 B840.050

The other compounds in the Examples showed IC₅₀ activities in themembrane cyclase assay less than about 500 μM.

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but not limitedto, printed publications, and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

1. A compound of Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: A and B are independently C₁₋₃ alkylene optionally substituted with 1 to 4 methyl groups; D is O, S, S(O), S(O)₂, CR₂R₃ or N—R₂; V is selected from the group consisting of C₁₋₃ alkylene, ethynylene and C₁₋₂ heteroalkylene wherein each are optionally substituted with 1 to 4 substituents selected from the group consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen; or V is absent; W is NR₄, O, S, S(O) or S(O)₂; or W is absent; X is N or CR₅; Y is N or CR₆; Z is selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₄₋₈ diacylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl, heterocyclic, heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl, wherein C₁₋₈ alkyl and C₁₋₅ acyl are each optionally substituted with 1, 2, 3 or 4 groups selected from the group consisting of C₁₋₅ acyl, C₁₋₆ acyloxy, C₁₋₄ alkoxy, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro; or Z is a group of Formula (A):

wherein: R₇ is H, C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₃ is H, nitro or nitrile; Ar₁ is aryl or heteroaryl wherein each are optionally substituted with R₉-R₁₃; R₁ is selected from the group consisting of H, C₁₋₃ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio and hydroxyl; R₂ is selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, hydroxyl and phenyl; and wherein C₁₋₈ alkyl, heteroaryl and phenyl are each optionally substituted with 1 to 5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkylene, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino and nitro; or R₂ is —Ar₂-Ar₃ wherein Ar₂ and Ar₃ are independently aryl or heteroaryl each optionally substituted with 1 to 5 substituents selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or R₂ is a group of Formula (B):

wherein: R₁₄ is C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₁₅ is F, Cl, Br or CN; or R₂ is a group of Formula (C):

wherein: G is C═O, CR₁₆R₁₇, O, S, S(O), S(O)₂; where R₁₆ and R₁₇ are independently H or C₁₋₈ alkyl; and Ar₄ is phenyl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro; R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy, halogen or hydroxyl; R₄ is H or C₁₋₈ alkyl; R₅ and R₆ are independently H, C₁₋₈ alkyl or halogen; R₉ is selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, arylsulfonyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl, sulfonamide and sulfonic acid, and wherein C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfonamide, alkylsulfonyl, arylsulfonyl, heteroaryl, phenoxy and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro and phenyl; or R₉ is a group of Formula (D):

wherein: “p” and “r” are independently 0, 1, 2 or 3; and R₁₈ is H, C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein the heteroaryl and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl; and R₁₀-R₁₃ are independently selected form the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₄ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl and nitro; or two adjacent R₁₀-R₁₁ groups together with Ar₁ form a 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclic group wherein the 5, 6 or 7 membered group is optionally substituted with halogen.
 2. The compound according to claim 1 wherein W is NR₄.
 3. The compound according to claim 2 wherein R₄ is H.
 4. The compound according to claim 2 wherein R₄ is CH₃ or CH₂CH₃.
 5. The compound according to claim 1 wherein W is O.
 6. The compound according to claim 1 wherein W is S.
 7. The compound according to claim 1 wherein W is absent.
 8. The compound according to claim 1 wherein W is absent and V is ethynylene.
 9. The compound according to claim 1 wherein V is —CH₂— or —CH₂CH₂—.
 10. The compound according to claim 1 wherein V is —OCH₂CH₂—.
 11. The compound according to claim 1 wherein V is absent.
 12. The compound according to claim 1 wherein A is ethylene and B is methylene.
 13. The compound according to claim 1 wherein A is propylene and B is methylene.
 14. The compound according to any claim 1 wherein A and B are both ethylene wherein A and B are optionally substituted with 1 to 4 methyl groups.
 15. The compound according to claim 1 wherein D is O, S, S(O) or S(O)₂.
 16. The compound according to claim 1 wherein D is CR₂R₃.
 17. The compound according to claim 16 wherein R₂ is selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen and hydroxyl.
 18. The compound according to claim 17 wherein R₂ is selected from the group consisting of C(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂CH₂CH₂CH₃, OC(O)CH₃, OC(O)CH₂CH₃, OC(O)CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂(CH₂)₂CH₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, CH₂(CH₂)₃CH₃, C(O)NH₂, CO₂CH₃, CO₂CH₂CH₃, CO₂CH₂CH₂CH₃, CO₂CH(CH₃)₂, CO₂CH₂(CH₂)₂CH₃, and CO₂H.
 19. The compound according to claim 17 wherein R₂ is selected from the group consisting of S(O)₂CH₃, S(O)₂CH₂CH₃, S(O)₂CH₂CH₂CH₃, S(O)₂CH(CH₃)₂, S(O)₂CH₂(CH₂)₂CH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, and F.
 20. The compound according to claim 16 wherein R₂ is C₁₋₈ alkyl, or heteroaryl each optionally substituted with 1 to 5 substituents selected from the group consisting of C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfonyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkylene, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, and hydroxyl.
 21. The compound according to claim 20 wherein R₂ is selected from the group consisting of CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₂CH₃, CH₂OCH(CH₃)₂, CH₂OCH₂CH(CH₃)₂, CH₂CO₂H, CH₂CH₂CO₂H, CH₂OH, CH₂CH₂OH and CH₂CH₂CH₂OH.
 22. The compound according to claim 20 wherein R₂ is selected from the group consisting of CH₂S(O)₂CH₃, CH₂S(O)₂CH₂CH₃, CH₂S(O)₂CH₂CH₂CH₃, CH₂S(O)₂CH(CH₃)₂, CH₂S(O)₂CH₂(CH₂)₂CH₃, CH₂CH₂S(O)₂CH₃, CH₂CH₂S(O)₂CH₂CH₃, CH₂CH₂S(O)₂CH₂CH₂CH₃, CH₂CH₂S(O)₂CH(CH₃)₂, CH₂CH₂S(O)₂CH₂(CH₂)₂CH₃, CH₂OCH₂-cyclopropyl, CH₂OCH₂-cyclobutyl, CH₂OCH₂-cyclopentyl, and CH₂OCH₂-cyclohexyl.
 23. The compound according to claim 20 wherein R₂ is selected from the group consisting of 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl, 3-isopropyl-1,2,4-oxadiazol-5-yl, 3-propyl-1,2,4-oxadiazol-5-yl, 3-t-butyl-1,2,4-oxadiazol-5-yl, and 3-cyclopropyl-1,2,4-oxadiazol-5-yl.
 24. The compound according to claim 16 wherein R₂ is —Ar₂-Ar₃ wherein Ar₂ and Ar₃ are independently aryl or heteroaryl each optionally substituted with 1 to 5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro.
 25. The compound according to claim 24 wherein Ar₂ is a heteroaryl and Ar₃ is phenyl.
 26. The compound according to claim 16 wherein R₂ is Formula (C):

wherein: G is C═O, CR₁₆R₁₇, O, S, S(O), S(O)₂; wherein R₁₆ and R₁₇ are independently H or C₁₋₂ alkyl; and Ar₄ is phenyl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, and halogen.
 27. The compound according to claim 26 wherein G is C═O, CH₂ or O.
 28. The compound according to claim 26 wherein G is S, S(O) or S(O)₂.
 29. The compound according claim 26 wherein Ar₄ is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.
 30. The compound according claim 26 wherein Ar₄ is 2-pyridyl.
 31. The compound according to claim 26 wherein R₁₆ and R₁₇ are both H.
 32. The compound according to claim 16 wherein R₃ is H.
 33. The compound according to claim 1 wherein D is N—R₂.
 34. The compound according to claim 33 wherein R₂ is H, or carbo-C₁₋₆-alkoxy.
 35. The compound according to claim 34 wherein R₂ is selected from the group consisting of CO₂CH₃, CO₂CH₂CH₃, CO₂CH₂CH₂CH₃, CO₂CH(CH₃)₂ and CO₂CH₂(CH₂)₂CH₃.
 36. The compound according to claim 33 wherein R₂ is C₁₋₈ alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of C₁₋₄ alkylsulfonyl, carbo-C₁₋₆-alkoxy, and carboxy.
 37. The compound according to claim 36 wherein R₂ is CH₂CO₂Et, or CH₂CH₂CO₂H.
 38. The compound according to claim 36 wherein R₂ is selected from the group consisting of CH₂CH₂S(O)₂CH₃, CH₂CH₂S(O)₂CH₂CH₃, CH₂CH₂S(O)₂CH₂CH₂CH₃, CH₂CH₂S(O)₂CH(CH₃)₂ and CH₂CH₂S(O)₂CH₂(CH₂)₂CH₃.
 39. The compound according to claim 1 wherein Z is selected from the group consisting of C₁₋₅ acyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, amino, cyano, C₄₋₈ diacylamino, C₂₋₆ dialkylsulfonamide, formyl, halogen, heterocyclic, and nitro wherein C₁₋₈ alkyl and C₁₋₅ acyl are each optionally substituted with 1, or 2 groups selected from the group consisting of C₂₋₄ dialkylamino, hydroxy, and halogen.
 40. The compound according to claim 39 wherein Z is selected from the group consisting of nitro, amino, formyl, NHC(O)CF₃, Br, NHC(O)CH₃, N(C(O)CH₃)₂, N(S(O)₂CH₃)₂, CH₃, [1,3]dioxolan-2-yl, CH₂OH, CH₂N(CH₃)₂, and C(O)CH₃.
 41. The compound according to claim 1 wherein R₁ is selected from the group consisting of H, C₁₋₈ alkyl, and amino.
 42. The compound according to claim 1 wherein Ar₁ is phenyl optionally substituted with R₉-R₁₃.
 43. The compound according to claim 42 wherein R₉ is selected from the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, arylsulfonyl, C₂₋₆ dialkylamino, C₂₋₆ dialkylsulfonamide, and carboxamide.
 44. The compound according to claim 43 wherein R₉ is selected from the group consisting of C(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂CH₂CH₂CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, CH₂(CH₂)₃CH₃, CH₂(CH₂)₄CH₃, CH₂(CH₂)₅CH₃, C(O)NHCH₃, C(O)NHCH₂CH₃, C(O)NHCH₂CH₂CH₃, C(O)NHCH(CH₃)₂, C≡CH, S(O)₂NHCH₃, S(O)₂NHCH₂CH₃, S(O)₂NHCH₂CH₂CH₃, S(O)₂NHCH(CH₃)₂, S(O)₂NHCH₂(CH₂)₂CH₃, S(O)₂NHCH(CH₃)CH₂CH₃, S(O)₂N(CH₃)₂, S(O)₂N(Et)(CH₃), S(O)₂CH₃, S(O)₂CH₂CH₃, S(O)₂CH₂CH₂CH₃, S(O)₂CH(CH₃)₂, S(O)₂CH₂(CH₂)₂CH₃, S(O)₂CH(CH₃)CH₂CH₃, SCH₃, SCH₂CH₃, SCH₂CH₂CH₃, SCH(CH₃)₂, SCH₂(CH₂)₂CH₃, amino, S(O)₂Ph, N(CH₃)₂, N(CH₃)(Et), N(Et)₂ and C(O)NH₂.
 45. The compound according to claim 42 wherein R₉ is selected from the group consisting of cyano, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfonyl, and C₁₋₄ haloalkylthio.
 46. The compound according to claim 45 wherein R₉ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cl, F, Br, OCF₃, OCHF₂, OCH₂CF₃, CF₃, CHF₂, CH₂CF₃, SCF₃, SCHF₂ and SCH₂CF₃.
 47. The compound according to claim 42 wherein R₉ is selected from the group consisting of heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxy, C₄₋₇ oxo-cycloalkyl, phenoxy and phenyl.
 48. The compound according to claim 47 wherein R₉ is selected from the group consisting of morpholin-4-yl, thiomorpholin-4-yl, 1-oxo-1λ⁴-thiomorpholin-4-yl, 1,1-Dioxo-1λ⁶-thiomorpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-propyl-piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl, 2,5-dioxo-imidazolidin-4-yl, 2,4-dioxo-thiazolidin-5-yl, 4-oxo-2-thioxo-thiazolidin-5-yl, 3-methyl-2,5-dioxo-imidazolidin-4-yl, 3-methyl-2,4-dioxo-thiazolidin-5-yl, 3-methyl-4-oxo-2-thioxo-thiazolidin-5-yl, 3-ethyl-2,5-dioxo-imidazolidin-4-yl, 3-ethyl-2,4-dioxo-thiazolidin-5-yl, and 3-ethyl-4-oxo-2-thioxo-thiazolidin-5-yl.
 49. The compound according to claim 47 wherein R₉ is selected from the group consisting of 1H-imidazol-4-yl, [1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl, pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl, oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl, [1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl, tetrazol-1-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and [1,2,3]thiadiazol-4-yl.
 50. The compound according to claim 42 wherein R₉ is C₁₋₈ alkyl or C₁₋₄ alkoxy optionally substituted with 1 to 5 substituents selected independently from the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, and hydroxyl.
 51. The compound according to claim 50 wherein R₉ is selected from the group consisting of CH₂OCH₃, CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃, CH₂OCH(CH₃)₂, CH₂OCH₂(CH₂)₂CH₃, CH₂CH₂OCH₃, CH₂CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₂CH₃, CH₂CH₂OCH(CH₃)₂ and CH₂CH₂OCH₂(CH₂)₂CH₃.
 52. The compound according to claim 42 wherein R₉ is of Formula (D):

wherein: “p” and “r” are independently 0, or 1; and R₁₈ is H, carbo-C₁₋₆-alkoxy, heteroaryl or phenyl, and wherein the heteroaryl and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl.
 53. The compound according to claim 52 wherein p=0 and r=0.
 54. The compound according to claim 53 wherein R₁₈ is phenyl optionally substituted with 1 to 5 substituents selected independently from the group consisting of C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl.
 55. The compound according to claim 52 wherein p=0 and r=1.
 56. The compound according to claim 55 wherein R₁₈ is carbo-C₁₋₆-alkoxy or carboxy.
 57. The compound according to any one of claims 43 wherein R₉ is substituted at the para position on the phenyl.
 58. The compound according claim 42 wherein R₁₀-R₁₃ are independently selected from the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy and C₁₋₄ haloalkyl.
 59. The compound according to claim 42 wherein one or two R₁₀-R₁₃ groups are independently halogen.
 60. The compound according to claim 42 wherein two adjacent R₁₀-R₁₁ groups together with the phenyl form a 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclic group wherein the 5, 6 or 7 membered group is optionally substituted with halogen.
 61. The compound according to claim 60 wherein the heterocyclic group together with the phenyl group is a 2,3-dihydro-benzofuran-5-yl, benzo[1,3]dioxol-5-yl group, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,3-dihydro-benzo[1,4]dioxin-2-yl group, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl group.
 62. The compound according to claim 1 wherein Ar₁ is heteroaryl optionally substituted with R₉-R₁₃.
 63. The compound according to claim 62 wherein R₉ is selected from the group consisting of C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonyl, C₁₋₄ haloalkyl, hydroxy, halogen, and phenyl.
 64. The compound according to claim 63 wherein R₉ is selected from the group consisting OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, CH₂(CH₂)₃CH₃, CH₂(CH₂)₄CH₃, CH₂(CH₂)₅CH₃, C(O)NHCH₃, C(O)NHCH₂CH₃, C(O)NHCH₂CH₂CH₃, C(O)NHCH(CH₃)₂, C(O)NHCH₂(CH₂)₂CH₃, S(O)₂CH₃, S(O)₂CH₂CH₃, S(O)₂CH₂CH₂CH₃, S(O)₂CH(CH₃)₂, Cl, F, Br, CF₃, CHF₂, CH₂CF₃, and hydroxy.
 65. The compound according to claim 62 wherein R₁₀-R₁₃ are independently C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy and C₁₋₄ haloalkyl.
 66. The compound according to claim 62 wherein one or two R₁₀-R₁₃ groups are independently halogen.
 67. The compound according to claim 1 wherein X is N and Y is CH.
 68. The compound according to claim 1 wherein X is N and Y is CF.
 69. The compound according to claim 1 wherein X is CH and Y is N.
 70. The compound according to claim 1 wherein X and Y are N.
 71. The compound according to claim 1 wherein X and Y are CH.
 72. The compound according to claim 1 wherein X is CH and Y are CF.
 73. The compound according to claim 1 wherein said compound is selected from the group consisting of: 1-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(Benzo[1,2,5]oxadiazol-5-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[5-Amino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; Propionic acid 1-[2-amino-5-formyl-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidin-4-yl ester; 4-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperazine-1-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid methyl ester; 2,6-Dimethyl-4-[6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-morpholine; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-3-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethylamide; 1-[6-(2-Methyl-5-phenyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-piperidin-1-yl-pyrimidine; 1-[5-Nitro-6-(2-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Bromo-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Acetylamino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Diacetylamino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid; 1-{5-Nitro-6-[2-(2-trifluoromethyl-phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{5-Nitro-6-[2-(3-trifluoromethyl-phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[5-Di-(methanesulfonyl)amino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Methyl-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(2-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,5-Dimethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Bromo-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Chloro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Carbamoyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2-Methoxy-ethyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Cyclopentyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-pyrrol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Benzoyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(4-Hydroxy-benzenesulfonyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4′-Cyano-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(5-Hydroxy-pyrimidin-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-sulfo-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Carbamoylmethyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4′-Methoxy-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2,5-Dioxo-imidazolidin-4-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 4-(4,4-Difluoro-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 1-{5-Nitro-6-[4-(4-oxo-cyclohexyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{5-Nitro-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-propionyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxy ic acid ethyl ester; 1-{6-[4-(2-Hydroxy-ethyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; {4-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone; 3-{4-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionic acid methyl ester; 2-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-5-ethanesulfonyl-phenylamine; 4-(4-Cyclopentyl-phenoxy)-6-(4,4-difluoro-piperidin-1-yl)-5-nitro-pyrimidine; 1-[6-(2,6-Dichloro-4-methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(4-Chloro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(4-Hydroxy-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Cyanomethyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; (4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone; 4-(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one; 3-(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-3-oxo-propionic acid methyl ester; 4-(4-Methyl-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-(4-Bromo-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid amide; 1-[5-Nitro-6-(2-oxo-2H-chromen-6-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(2-oxo-benzo[1,3]oxathiol-6-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(9H-Carbazol-2-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(9-oxo-9H-fluoren-2-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{5-Amino-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-[4-(3-Oxo-butyl)-phenoxy]-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{5-Amino-6-[4-(hydroxy-phenyl-methyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Benzoyl-5-methoxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(6-Chloro-pyridin-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(Benzo[1,3]dioxol-5-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Benzyloxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3-Morpholin-4-yl-phenoxy)-5-nitro-pyrimidin-4-34]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethoxy-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Benzoyl-phenoxy)-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; {4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone; {4-Methoxy-2-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone; 4-{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2-one; 5-Nitro-4-(4-propyl-piperidin-1-yl)-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine; 3-{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionic acid methyl ester; 5-Ethanesulfonyl-2-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenylamine; 1-[6-(4-Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3-Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 2-{1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-ethanol; 3-{1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-propionic acid; 4-[4-(4-Methyl-benzyl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-(3-Methanesulfonyl-pyrrolidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidine; 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine; 4′-(4-Benzoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carboxylic acid ethyl ester; 3′-Nitro-4′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carboxylic acid ethyl ester; 4′-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carboxylic acid ethyl ester; 4′-(2-Amino-4-ethanesulfonyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester; 4′-(4-Imidazol-1-yl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carboxylic acid ethyl ester; 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-trifluoromethyl-piperidin-1-yl)-pyrimidine; 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidine; 1-[6-(3-Ethynyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Chloro-2-fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,4-Difluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Bromo-2-fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 4-(3-Ethynyl-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; 4-(4-Chloro-2-fluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; 4-(2,4-Difluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; 4-(4-Bromo-2-fluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; 3′-Nitro-2′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid ethyl ester; 4-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-yloxy)-phenyl]-butan-2-one; 2′-(4-Benzoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid ethyl ester; 4-(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one; [4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-2′-yloxy)-phenyl]-phenyl-methanone; 4-(4-{5-Nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one; 4-(4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one; (4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone; 1-{6-[4-(4-Fluoro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; (4-Fluoro-phenyl)-{4-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-methanone; 4-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-(4-Methoxymethyl-piperidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-{4-[6-(4-Methoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one; 4-[4-(2-Methoxy-ethyl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-{4-[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one; 4-(2,4-Difluoro-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine; (4-Methoxy-2-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone; 4-(2,4-Difluoro-phenoxy)-6-(4-ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidine; 4-{4-[6-(4-Cyclopropylmethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one; 4-{4-[5-Nitro-6-(4-propoxymethyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2-one; 1-{4-[6-(4-Methoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-ethanone; 4-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-butan-2-one; 1-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-ethanone; {4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-phenyl-methanone; 3-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-3-oxo-propionic acid methyl ester; 4-{4-[6-(4-Butoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one; 4-{4-[6-(4-Isobutoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one; (4-Fluoro-phenyl)-[4-(3′-nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-yloxy)-phenyl]-methanone; 4-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-yloxy)-phenyl]-butan-2-one; 3′-Nitro-4-propyl-4′-(4-[1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl; 1-{2-Nitro-3-[4-(3-oxo-butyl)-phenoxy]-phenyl}-piperidine-4-carboxylic acid ethyl ester; 1-[3-(4-Benzoyl-phenoxy)-2-nitro-phenyl]-piperidine-4-carboxylic acid ethyl ester; {4-[6-(4-Ethoxy-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-(4-fluoro-phenyl)-methanone; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-ol; 1-[6-(4-Acetyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; (1-{6-[4-(4-Fluoro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidin-4-yl)-(4-fluoro-phenyl)-methanone; 4-(4-{6-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one; 4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-cyclohexyl]-pyrimidine; 4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-4-ylsulfanyl)-cyclohexyl]-pyrimidine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine-5-carbonitrile; 5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)pyrimidine-5-carbaldehyde; 5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carbaldehyde; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carboxylic acid; [4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-yl]-methanol; [4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-ylmethyl]-dimethyl-amine; 4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-(4-phenylsulfanyl-cyclohexyl)-pyrimidine; 4-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl-pyridin-3-yloxy)-5-nitro-pyrimidine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-2-methyl-pyrimidine-5-carbonitrile; and 1-[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidin-5-yl]-ethanone; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
 74. The compound according to claim 1 wherein said compound is selected from the group consisting of: 1-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3,4,5-trimethoxy-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; (5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)-(3-trifluoromethyl-benzyl)-amine; 1-[5-Nitro-6-(2-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; (5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)-(2-trifluoromethyl-benzyl)-amine; (5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)-(4-trifluoromethyl-benzyl)-amine; 1-[5-Amino-6-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Amino-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Bromo-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(Methyl-phenyl-amino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Difluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dichloro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Bromo-4-trifluoromethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2-Fluoro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(Ethyl-phenyl-amino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(4-Chloro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Difluoromethyl-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(6-Fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(Morpholine-4-sulfonyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,2-Difluoro-benzo[1,3]dioxol-4-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,2-Difluoro-benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(1,1-Dioxo-1H-1λ⁶-benzo[b]thiophen-6-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(Furan-3-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[2-(4-Methoxy-phenoxy)-ethylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[2-(5-Methoxy-1H-indol-3-yl)-ethylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; (3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; (3-Fluoro-phenyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; (3-Methoxy-phenyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; 1-{6-[(3-Fluoro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Benzoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Dimethylsulfamoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Bis-trifluoromethyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dimethoxy-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(3,4,5-trimethoxy-benzyl)-amine; (3,5-Dim ethoxy-benzyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; (4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-ylamino}-phenyl)-phenyl-methanone; (4-{5-Nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidin-4-ylamino}-phenyl)-phenyl-methanone; 1-[6-(4-Cyano-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-sec-Butyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Heptyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 2′-(4-Benzoyl-phenylamino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-pentyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(3-Carboxy-propyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(Cyano-phenyl-methyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Cyclohexyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine; [5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine; {5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine; (2-Fluoro-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine; {6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine; 1-{5-Nitro-6-[4-(4-trifluoromethyl-phenoxy)-phenylamino]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; {6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-phenyl)-amine; {6-[4-(2-Methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine; (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl-piperidin-1-yl]-pyrimidin-4-yl}-amine; (3-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine; Benzo[1,3]dioxol-5-yl-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; (4-Fluoro-phenyl)-{1-[5-nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidin-4-yl}-methanone; [5-Nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine; (4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone; 1-[6-(2-Methyl-5-phenyl-2H-pyrazol-3-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; (4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine; {6-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine; (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyrimidin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)-{6-[4-(4-methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine; [6-(4-Benzenesulfonyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine; {4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperazin-1-yl}-acetic acid ethyl ester; (2-Fluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine; 2-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine; {6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine; (6-{4-[5-(4-Fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-piperidin-1-yl}-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine; (4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-pyridin-2-ylmethyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; 1-{6-[4-(4,5-Dichloro-imidazol-1-yl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; Benzo[1,3]dioxol-5-yl-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine; (4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone; {1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-(4-fluoro-phenyl)-methanone; (2,3-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine; (2,4-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine; (2,5-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine; 1-[6-(4-Benzenesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(2-trifluoromethyl-3H-benzoimidazol-5-ylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{5-Nitro-6-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenylamino]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; {6-[4-(4-Iodo-phenoxy)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine; (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine; {6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine; (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine; {6-[4-(3-Cyclopropylmethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine; {6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine; {6-[4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfinyl-phenylamino)-pyrimidine-5-carbonitrile; (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(4-trifluoromethoxy-phenoxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile; 1-{1-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one; 1-{1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one; {6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine; {6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine; [6-(4-Benzofuran-2-yl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine; 4-(3-Fluoro-4-methanesulfonyl-phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile; {6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(5-methanesulfonyl-pyridin-2-yl)-amine; (3-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine; {6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(6-methanesulfonyl-pyridin-3-yl)-amine; 4-(2,3-Difluoro-phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile; 4-(2,5-Difluoro-phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile; 4-(4-Hexanoyl-piperidin-1-yl)-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile; 4-(4-Hexanoyl-piperidin-1-yl)-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile; 1-[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidin-5-yl]-ethanone; and 1-[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
 75. The compound according to claim 1 wherein said compound is selected from the group consisting of: 1-(5-Nitro-6-phenyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-(6-Naphthalen-2-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(6-Benzofuran-5-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 4-(4-Butyl-piperidin-1-yl)-6-furan-3-yl-5-nitro-pyrimidine; 1-[6-(3-Chloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,6-Dimethoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(6-Naphthalen-1-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methylsulfanyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(2′,4′-Dihydroxy-5-nitro-[4,5′]bipyrimidinyl-6-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Bis-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(6-Dibenzothiophen-4-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dimethyl-isoxazol-4-yl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(5-Nitro-6-thiophen-2-yl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dichloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(6-Dibenzofuran-4-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dimethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Acetyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Ethanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Fluoro-biphenyl-4-yl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2-Carboxy-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid methyl ester; and 1-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
 76. The compound according to claim 1 wherein said compound is selected from the group consisting of: 1-[5-Nitro-6-(2-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(5-Nitro-6-phenylethynyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(5-Nitro-6-m-tolylethynyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Fluoro-phenylethynyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; and 1-[5-Amino-6-(3-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
 77. The compound according to claim 1 wherein said compound is 5-Nitro-4-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine or a pharmaceutically acceptable salt, hydrate or solvate thereof.
 78. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier.
 79. A method for prophylaxis or treatment of a metabolic disorder in an individual comprising administering to the individual a therapeutically effective amount of a compound according to claim
 1. 80. The method according to claim 79 wherein the metabolic disorder is type I, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X or metabolic syndrome.
 81. The method according to claim 79 wherein the metabolic disorder is type II diabetes.
 82. A method for controlling or decreasing weight gain of an individual comprising administering to the individual a therapeutically effective amount of a compound according to claim
 1. 83. A method of modulating a RUP3 receptor comprising contacting the receptor with a compound according to claim
 1. 84. A method of modulating a RUP3 receptor in an individual comprising contacting the receptor with a compound according to claim
 1. 85. The method of modulating the RUP3 receptor according to claim 83 wherein the compound is an agonist.
 86. The method of modulating the RUP3 receptor according to claim 83 wherein the compound is an inverse agonist.
 87. The method of modulating the RUP3 receptor according to claim 84 wherein the modulation of the RUP3 receptor is prophylaxis or treatment of a metabolic disorder.
 88. The method of modulating the RUP3 receptor according to claim 87 wherein the metabolic disorder is type I, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X or metabolic syndrome.
 89. The method of modulating the RUP3 receptor according to claim 87 wherein the metabolic disorder is type II diabetes.
 90. The method of modulating the RUP3 receptor according to claim 84 wherein the modulation of the RUP3 receptor controls or reduces weight gain of the individual.
 91. The method according to claim 84 wherein the individual is a mammal.
 92. The method according to claim 91 wherein the mammal is a human. 93-99. (canceled)
 100. The method of producing a pharmaceutical composition comprising admixing at least one compound according to claim 1 and a pharmaceutically acceptable carrier. 